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Signaling and Signaling Pathways
Posted in Biological Networks, Gene Regulation and Evolution, Biomedical Measurement Science, Calcium Signaling, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Curation methodology, Cytoskeleton, Developmental biology, Endocrine Diseases, Enzyme Induction, Epigenetics and Cardiovascular Risks, Evolutionary cognition, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, Human Immune System in Health and in Disease, Ionic Transporters Na+, Metabolomics, Na-K transport, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmacotherapy and Cell Activity, Proteomics, Technology Advance Assessment of, tagged direct cell contact, distant effects, Intercellular (Paracellular) route, intercellular junctions, paracrine and juxtacrine, protein conformation, signaling, signaling pathways, surface charges on August 12, 2014| Leave a Comment »
Signaling and Signaling Pathways
Curator: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/8-9-2014/Signaling and Signaling Pathways
This portion of the discussion is a series of articles on signaling and signaling pathways. Many of the protein-protein interactions or protein-membrane interactions and associated regulatory features have been referred to previously, but the focus of the discussion or points made were different. I considered placing this after the discussion of proteins and how they play out their essential role, but this is quite a suitable place for a progression to what follows. This is introduced by material taken from Wikipedia, which will be followed by a series of mechanisms and examples from the current literature, which give insight into the developments in cell metabolism, with the later goal of separating views introduced by molecular biology and genomics from functional cellular dynamics that are not dependent on the classic view. The work is vast, and this discussion does not attempt to cover it in great depth. It is the first in a series.
- Signaling and signaling pathways
- Signaling transduction tutorial.
- Carbohydrate metabolism
- Lipid metabolism
- Protein synthesis and degradation
- Subcellular structure
- Impairments in pathological states: endocrine disorders; stress hypermetabolism; cancer.
Signal transduction
(From Wikipedia, the free encyclopedia)
http://en.wikipedia.org/wiki/File:Signal_transduction_publications_graph.jpeg
Signal_transduction_pathways.svg
Signal transduction occurs when an extracellular signaling[1] molecule activates a specific receptor located on the cell surface or inside the cell. In turn, this receptor triggers a biochemical chain of events inside the cell, creating a response.[2] Depending on the cell, the response alters the cell’s metabolism, shape, gene expression, or ability to divide.[3] The signal can be amplified at any step. Thus, one signaling molecule can cause many responses.[4]
In 1970, Martin Rodbell examined the effects of glucagon on a rat’s liver cell membrane receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and stimulated the G-protein, which strongly influenced the cell’s metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell.[5] For this, he shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman.
Signal_transduction_publications_graph
The earliest MEDLINE entry for “signal transduction” dates from 1972.[6] Some early articles used the terms signal transmission and sensory transduction.[7][8] In 2007, a total of 48,377 scientific papers—including 11,211 e review papers—were published on the subject. The term first appeared in a paper’s title in 1979.[9][10] Widespread use of the term has been traced to a 1980 review article by Rodbell:[5][11] Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s.[12]
Notch-mediated juxtacrine signal between adjacent cells.
Signal transduction involves the binding of extracellular signaling molecules and ligands to cell-surface receptors that trigger events inside the cell. The combination of messenger with receptor causes a change in the conformation of the receptor, known as receptor activation. This activation is always the initial step (the cause) leading to the cell’s ultimate responses (effect) to the messenger. Despite the myriad of these ultimate responses, they are all directly due to changes in particular cell proteins. Intracellular signaling cascades can be started through cell-substratum interactions; examples are the integrin that binds ligands in the extracellular matrix and steroids.[13] Most steroid hormones have receptors within the cytoplasm and act by stimulating the binding of their receptors to the promoter region of steroid-responsive genes.[14] Examples of signaling molecules include the hormone melatonin,[15] the neurotransmitter acetylcholine[16] and the cytokine interferon γ.[17]
Signal transduction cascades amplify the signal output
Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include photons hitting cells in the retina of the eye,[20] and odorants binding to odorant receptors in the nasal epithelium.[21] Certain microbial molecules, such as viral nucleotides and protein antigens, can elicit an immune system response against invading pathogens mediated by signal transduction processes. This may occur independent of signal transduction stimulation by other molecules, as is the case for the toll-like receptor. It may occur with help from stimulatory molecules located at the cell surface of other cells, as with T-cell receptor signaling. Unicellular organisms may respond to environmental stimuli through the activation of signal transduction pathways. For example, slime molds secrete cyclic adenosine monophosphate upon starvation, stimulating individual cells in the immediate environment to aggregate,[22] and yeast cells use mating factors to determine the mating types of other cells and to participate in sexual reproduction.[23] Receptors can be roughly divided into two major classes: intracellular receptors and extracellular receptors.
Extracellular
Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the conformation of the inside part of the receptor.[24] These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.
In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include tyrosine kinase and phosphatases. Some of them create second messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adaptor proteins that facilitate signalling protein interactions and coordination of signalling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules.
Many adaptor proteins and enzymes activated as part of signal transduction possess specialized protein domains that bind to specific secondary messenger molecules. For example, calcium ions bind to the EF hand domains of calmodulin, allowing it to bind and activate calmodulin-dependent kinase. PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.
G protein-coupled
G protein-coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. Many receptors are in this family, including adrenergic receptors and chemokine receptors.
Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling
Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; it exists as a heterotrimer consisting of Gα, Gβ, and Gγ.[25] Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation exposes sites on the subunits that can interact with other molecules.[26] The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such as phospholipases and ion channels, the latter permitting the release of second messenger molecules.[27] The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity.
A study was conducted where a point mutation was inserted into the gene encoding the chemokine receptor CXCR2; mutated cells underwent a malignant transformation due to the expression of CXCR2 in an active conformation despite the absence of chemokine-binding. This meant that chemokine receptors can contribute to cancer development.[28]
Tyrosine and histidine kinase
Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligands; examples include growth factor receptors such as the insulin receptor.[29] To perform signal transduction, RTKs need to form dimers in the plasma membrane;[30] the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation of tyrosines within the domains of the RTKs, causing conformational changes. Subsequent to this, the receptors’ kinase domains are activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism.[29]
As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf families, referred to collectively as small G proteins. They act as molecular switches usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors such as SOS1. Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor’s initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively activate state; such mutated genes may act as oncogenes.[31]
Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue.[32]
Integrin
integrin-mediated signal transduction
An overview of integrin-mediated signal transduction, adapted from Hehlgens et al. (2007).[33]
Integrins are produced by a wide variety of cells; they play a role in cell attachment to other cells and the extracellular matrix and in the transduction of signals from extracellular matrix components such as fibronectin and collagen. Ligand binding to the extracellular domain of integrins changes the protein’s conformation, clustering it at the cell membrane to initiate signal transduction. Integrins lack kinase activity; hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase.[33] As shown in the picture to the right, cooperative integrin-RTK signalling determines the timing of cellular survival, apoptosis, proliferation, and differentiation.
Important differences exist between integrin-signalling in circulating blood cells and non-circulating cells such as epithelial cells; integrins of circulating cells are normally inactive. For example, cell membrane integrins on circulating leukocytes are maintained in an inactive state to avoid epithelial cell attachment; they are activated only in response to stimuli such as those received at the site of an inflammatory response. In a similar manner, integrins at the cell membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells (which are non-circulating) normally have active integrins at their cell membrane, helping maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal functioning.[34]
Toll gate
When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adaptor molecules are known to be involved in signaling, which are Myd88, TIRAP, TRIF, and TRAM.[35][36][37] These adapters activate other intracellular molecules such as IRAK1, IRAK4, TBK1[disambiguation needed], and IKKi that amplify the signal, eventually leading to the induction or suppression of genes that cause certain responses. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation.
Ligand-gated ion channel
A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to the opening of these channels induces action potentials, such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.
An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it acts as a second messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the synapse.
Ion transporters and channels in mammalian choroidal epithelium
Intracellular
Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the conformation of the inside part of the receptor.[24] These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.
Understanding these receptors and identifying their ligands and the resulting signal transduction pathways represent a major conceptual advance
intercellular signaling
conformational-rearrangements
membrane protein receptor binds with hormone
The multiple protein-dependent steps in signal transduction
In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include tyrosine kinase and phosphatases. Some of them create second messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adaptor proteins that facilitate signalling protein interactions and coordination of signalling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules.
Ca++ exchange
Many adaptor proteins and enzymes activated as part of signal transduction possess specialized protein domains that bind to specific secondary messenger molecules. For example, calcium ions bind to the EF hand domains of calmodulin, allowing it to bind and activate calmodulin-dependent kinase. PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.
G protein-coupled
G protein-coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. Many receptors are in this family, including adrenergic receptors and chemokine receptors.
membrane_receptor_g protein
intracellular_receptor_steroid
Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; it exists as a heterotrimer consisting of Gα, Gβ, and Gγ.[25] Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation exposes sites on the subunits that can interact with other molecules.[26] The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such as phospholipases and ion channels, the latter permitting the release of second messenger molecules.[27] The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity.
A study was conducted where a point mutation was inserted into the gene encoding the chemokine receptor CXCR2; mutated cells underwent a malignant transformation due to the expression of CXCR2 in an active conformation despite the absence of chemokine-binding. This meant that chemokine receptors can contribute to cancer development.[28]
Tyrosine and histidine kinase
Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligands; examples include growth factor receptors such as the insulin receptor.[29] To perform signal transduction, RTKs need to form dimers in the plasma membrane;[30] the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation of tyrosines within the domains of the RTKs, causing conformational changes. Subsequent to this, the receptors’ kinase domains are activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism.[29]
insulin-receptor-and-and-insulin-receptor-signaling-pathway-irs
receptors-regulators
phosphorylation-cascade
As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf families, referred to collectively as small G proteins. They act as molecular switches usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors such as SOS1. Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor’s initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively activate state; such mutated genes may act as oncogenes.[31]
Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue.[32]
Integrin
integrin-mediated signal transduction
An overview of integrin-mediated signal transduction, adapted from Hehlgens et al. (2007).[33]
Integrins are produced by a wide variety of cells; they play a role in cell attachment to other cells and the extracellular matrix and in the transduction of signals from extracellular matrix components such as fibronectin and collagen. Ligand binding to the extracellular domain of integrins changes the protein’s conformation, clustering it at the cell membrane to initiate signal transduction. Integrins lack kinase activity; hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase.[33] As shown in the picture to the right, cooperative integrin-RTK signalling determines the timing of cellular survival, apoptosis, proliferation, and differentiation.
Platelet signaling pathways
Protein ubiquitylation
ubiquitylation-is-a-multistep-reaction.
Important differences exist between integrin-signaling in circulating blood cells and non-circulating cells such as epithelial cells; integrins of circulating cells are normally inactive. For example, cell membrane integrins on circulating leukocytes are maintained in an inactive state to avoid epithelial cell attachment; they are activated only in response to stimuli such as those received at the site of an inflammatory response. In a similar manner, integrins at the cell membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells (which are non-circulating) normally have active integrins at their cell membrane, helping maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal functioning.[34]
Toll gate
When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adaptor molecules are known to be involved in signaling, which are Myd88, TIRAP, TRIF, and TRAM.[35][36][37] These adapters activate other intracellular molecules such as IRAK1, IRAK4, TBK1[disambiguation needed], and IKKi that amplify the signal, eventually leading to the induction or suppression of genes that cause certain responses. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation.
SignalTrans
Ligand-gated ion channel
A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to the opening of these channels induces action potentials, such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.
An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it acts as a second messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the synapse.
Ion transporters and channels in mammalian choroidal epithelium
Intracellular
Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are lipophilic hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, enabling gene transcription and protein production.
Signal Transduction
Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors of gene expression. All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor.
Signal transduction via these receptors involves little proteins, but the details of gene regulation by this method are not well-understood. Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus.
signal-transduction-in-protease-signaling-
protein changes in biological mechanisms
Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol; in the absence of steroids, they cling together in an aporeceptor complex containing chaperone or heatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden; activity can be enhanced by phosphorylation of serine residues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk.
Structure of the N-terminal domain of the yeast Hsp90 chaperone
Pincer movement of Hsp90 coupled to the ATPase cycle. NTD = N-terminal domain, MD = middle domain, CTD = C-terminal domain.
Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a precursor like retinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs; they repress their gene by binding to their specific DNA sequence when no ligand binds to them, and vice versa.
Certain intracellular receptors of the immune system are cytoplasmic receptors; recently identified NOD-like receptors (NLRs) reside in the cytoplasm of some eukaryotic cells and interact with ligands using a leucine-rich repeat (LRR) motif similar to TLRs. Some of these molecules like NOD2 interact with RIP2 kinase that activates NF-κB signaling, whereas others like NALP3 interact with inflammatory caspases and initiate processing of particular cytokines like interleukin-1β.[38][39]
Cell signaling
signaling pathjways map
Cell signalling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signalling, diseases may be treated effectively and, theoretically, artificial tissues may be created.
Traditional work in biology has focused on studying individual parts of cell signaling pathways. Systems biology research helps us to understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and flow of information. Such networks are complex systems in their organization and may exhibit a number of emergent properties. Long-range allostery is often a significant component of cell signaling events.[1]
Enzyme_Model allosterism
Classification
Signaling within, between, and among cells is subdivided into the following classifications:
- Intracrine signals are produced by the target cell that stay within the target cell.
- Autocrine signals are produced by the target cell, are secreted, and effect the target cell itself via receptors. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells.
- Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent.
transepithelial-electrogenic-ion-transport
calcium release calmodulin + ER
Ca++ exchange
Paracrine bidirectional cardiac fibroblast-myocyte crosstalk
- Paracrine signals target cells in the vicinity of the emitting cell. Neurotransmitters represent an example.
- Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body.
Notch-mediated juxtacrine signal between adjacent cells.
Notch-mediated juxtacrine signal between adjacent cells.
Some cell–cell communication requires direct cell–cell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allows for action potential propagation from the cardiac pacemaker region of the heart to spread and coordinately cause contraction of the heart.
The notch signaling mechanism is an example of juxtacrine signaling (also known as contact-dependent signaling) in which two adjacent cells must make physical contact in order to communicate. This requirement for direct contact allows for very precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.[5]
Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell.[6] Neurotransmitters represent another example of a paracrine signal. Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain.[7] Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.[8] Active species of oxygen and nitric oxide can also act as cellular messengers. This process is dubbed redox signaling.
Signaling Pathways
Cell Signaling Biology
Michael J. Berridge
Module 2
Cell Signaling Pathways
The nine membrane-bound adenylyl cyclases (AC1–AC9) have a similar domain structure. The single polypeptide has a tandem repeat of six transmembrane domains (TM) with TM1- -TM6 in one repeat and TM7- -TM12 in the other. Each TM cassette is followed by large cytoplasmic domains (C1 and C2), which contain the catalytic regions that convert ATP into cyclic AMP. As shown in the lower panel, the C1 and C2 domains come together to form a heterodimer. The ATP-binding site is located at the interface between these two domains. The soluble AC10 isoform lacks the transmembrane regions, but it retains the C1 and C2 domains that are responsible for catalysis
www.cellsignallingbiology.org http://www.biochemj.org/csb/002/csb002.pdf
Resources:
Elucidate Target-Specific Pathways With a Suite of Cellular Assays
DiscoveRx® offers a comprehensive collection of cell-based pathway indicator assays designed to detect activation or inhibition of complex signal transduction pathways in response to compound treatment. Based on the proven PathHunter® technology, These biosensor cell lines allow you to measure distinct events within a variety of pathways involved in compound toxicity, cholesterol metabolism, antioxidant function, DNA damage and ER stress. In combination with our biosensor cell lines with fast and simple chemiluminescent detection, DiscoveRx Pathway Signaling assays will help you generate cellular pathway selectivity profiles of your compounds without relying on reporter gene assays or complex phenotypic screens. – See more at: http://www.discoverx.com/targets/signaling-pathways?gclid=CPPrxrrli8ACFSdp7AodO2IADQ#sthash.OhK3iKl4.dpuf
GPCR Targets , Kinase Targets , Nuclear Receptors , Protease Targets , Epigenetic Targets , Signaling Pathways – See more at: http://www.discoverx.com/targets#sthash.KjwWEjjx.dpuf
DiscoveRx® offers a comprehensive collection of cell-based pathway indicator assays designed to detect activation or inhibition of complex signal transduction pathways in response to compound treatment. Based on the proven PathHunter® technology, These biosensor cell lines allow you to measure distinct events within a variety of pathways involved in compound toxicity, cholesterol metabolism, antioxidant function, DNA damage and ER stress. – See more at: http://www.discoverx.com/targets/signaling-pathways#sthash.ZTb5UXVO.dpuf
inhibitors of signal transduction pathway
Inhibitors of MAPK Signaling Pathway
jak-stat
Nrf2 signaling in ARE-mediated coordinated activation of defensive genes
Regulation of AMPK
metabolic pathways
On these resource pages you can find signaling pathway diagrams, research overviews, relevant antibody products, publications, and other research resources organized by topic. The pathway diagrams associated with these topics have been assembled by CST scientists and outside experts to provide succinct and current overviews of selected signaling pathways. Please send suggestions for developing new pathways to info@cellsignal.com. Protein nodes in each pathway diagram are linked to specific antibody product information or, optionally, to protein-specific listings in the PhosphoSitePlus® database of post-translational modifications.
http://www.cellsignal.com/common/content/content.jsp?id=science-pathways
http://www.cellsignal.com/common/content/content.jsp?id=pathways-akt-signaling
http://www.cellsignal.com/common/content/content.jsp?id=pathways-mtor-signaling
PI3K / Akt Signaling Overview
The serine/threonine kinase Akt/PKB exists as three isoforms in mammals. Akt1 has a wide tissue distribution, whereas Akt2 is found predominantly in muscle and fat cells and Akt3 is expressed in testes and brain. Akt regulates multiple biological processes including cell survival, proliferation, growth, and glycogen metabolism. Various growth factors, hormones, and cytokines activate Akt by binding their cognate receptor tyrosine kinase (RTK), cytokine receptor, or GPCR and triggering activation of the lipid kinase PI3K, which generates PIP3 at the plasma membrane. Akt binds PIP3 through its pleckstrin homology (PH) domain, resulting in translocation of Akt to the membrane. Akt is activated through a dual phosphorylation mechanism. PDK1, which is also brought to the membrane through its PH domain, phosphorylates Akt within its activation loop at Thr308. A second phosphorylation at Ser473 within the carboxy terminus is also required for activity and is carried out by the mTOR-rictor complex, mTORC2.
PTEN, a lipid phosphatase that catalyzes the dephosphorylation of PIP3, is a major negative regulator of Akt signaling. Loss of PTEN function has been implicated in many human cancers. Akt activity is also negatively regulated by the phosphatases PP2A and PHLPP, as well as by the chemical modulators wortmannin and LY294002, both of which are inhibitors of PI3K.
Activated Akt phosphorylates a large number of downstream substrates containing the consensus sequence RXRXXS/T. One of its primary functions is to promote cell growth and protein synthesis through regulation of the mTOR signaling pathway. Akt directly phosphorylates and activates mTOR, as well as inhibits the mTOR inhibitor proteins PRAS40 and tuberin (TSC2). Combined, these actions promote cell growth and G1 cell cycle progression through signaling via p70 S6 Kinase and inhibition of 4E-BP1.
Phosphofructokinase mechanism
GSK-3 is a primary target of Akt and inhibitory phosphorylation of GSK-3α (Ser21) or GSK-3β (Ser9) has numerous cellular effects such as promoting glycogen metabolism, cell cycle progression, regulation of wnt signaling, and formation of neurofibrillary tangles in Alzheimers disease. Akt promotes cell survival directly by its ability to phosphorylate and inactivate several pro-apoptotic targets, including Bad, Bim, Bax, and the forkhead (FoxO1/3a) transcription factors. Akt also plays an important role in metabolism and insulin signaling. Insulin receptor signaling through Akt promotes Glut4 translocation through activation of AS160 and TBC1D1, resulting in increased glucose uptake. Akt regulates glycolysis through phosphorylation of PFK and hexokinase, and plays a significant role in aerobic glycolysis of cancer cells, also known as the Warburg Effect.
Aberrant Akt signaling is the underlying defect found in several pathologies. Akt is one of the most frequently activated kinases in human cancer as constitutively active Akt can promote unregulated cell proliferation. Abnormalities in Akt2 signaling can result in diabetes due to defects in glucose homeostasis. Akt is also a key player in cardiovascular disease through its role in cardiac growth, angiogenesis, and hypertrophy.
References
- Robey RB, Hay N (2009) Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Cancer Biol. 19(1), 25–31.
- Zhang S, Yu D (2010) PI(3)king apart PTEN’s role in cancer. Cancer Res. 16(17), 4325–30.
- Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Rev. Mol. Cell Biol. 12(1), 21–35.
- Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biophys. Acta 1813(11), 1978–86.
- Kloet DE, Burgering BM (2011) The PKB/FOXO switch in aging and cancer. Biophys. Acta 1813(11), 1926–37.
- Hers I, Vincent EE, Tavars JM (2011) Akt signalling in health and disease. Signal. 23(10), 1515–27.
- Wang H, Zhang Q, Wen Q, Zheng Y, Lazarovici P, Philip L, Jiang H, Lin J, Zheng W (2012) Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway. Signal. 24(1), 17–24.
- Dazert E, Hall MN (2011) mTOR signaling in disease. Opin. Cell Biol. 23(6), 744–55.
- Bayley JP, Devilee P (2012) The Warburg effect in 2012. Curr Opin Oncol 24(1), 62–7.
mTOR Signaling Pathway
Akt mTOR pathway
The mammalian target of rapamycin (mTOR) is an atypical serine/threonine kinase that is present in two distinct complexes. mTOR complex 1 (mTORC1) is composed of mTOR, Raptor, GβL (mLST8), and Deptor and is partially inhibited by rapamycin. mTORC1 integrates multiple signals reflecting the availability of growth factors, nutrients, or energy to promote either cellular growth when conditions are favorable or catabolic processes during stress or when conditions are unfavorable. Growth factors and hormones (e.g. insulin) signal to mTORC1 via Akt, which inactivates TSC2 to prevent inhibition of mTORC1. Alternatively, low ATP levels lead to the AMPK-dependent activation of TSC2 and phosphorylation of raptor to reduce mTORC1 signaling. Amino acid availability is signaled to mTORC1 via a pathway involving the Rag and Ragulator (LAMTOR1-3) proteins. Active mTORC1 has a number of downstream biological effects including translation of mRNA via the phosphorylation of downstream targets (4E-BP1 and p70 S6 Kinase), suppression of autophagy (Atg13, ULK1), ribosome biogenesis, and activation of transcription leading to mitochondrial metabolism or adipogenesis. The mTOR complex 2 (mTORC2) is composed of mTOR, Rictor, GβL, Sin1, PRR5/Protor-1, and Deptor and promotes cellular survival by activating Akt. mTORC2 also regulates cytoskeletal dynamics by activating PKCα and regulates ion transport and growth via SGK1 phosphorylation. Aberrant mTOR signaling is involved in many disease states including cancer, cardiovascular disease, and metabolic disorders.
Selected Reviews:
- Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N (2010) Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim. Biophys. Acta 1804(3), 433–9.
- Dunlop EA, Tee AR (2009) Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell. Signal. 21(6), 827–35.
- Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33(2), 67–75.
- Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J. Cell. Sci. 122(Pt 20), 3589–94.
- Neufeld TP (2010) TOR-dependent control of autophagy: biting the hand that feeds. Curr. Opin. Cell Biol. 22(2), 157–68.
- Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12(1), 21–35.
We would like to thank Carson Thoreen and Prof. David Sabatini, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, for reviewing this diagram. revised November 2012
Protein Folding
conformational-rearrangements
Pincer movement of Hsp90 coupled to the ATPase cycle. NTD = N-terminal domain, MD = middle domain, CTD = C-terminal domain.
Heat Shock Proteins (HSPs) form seven families (small HSPs (sHSPs), HSP10, 40, 60, 70, 90, and 100) of molecular chaperone proteins that play a central role in the cellular resistance to stress and actin organization. They are involved in the proper folding of proteins and the recognition and refolding of misfolded proteins. HSP expression is induced by a variety of environmental stresses, including heat, hypoxia, nutrient deficiency, free radicals, toxins, ischemia, and UV radiation. HSP27 is a member of the sHSP family. It is phosphorylated at Ser15, Ser78, and Ser82 by MAPKAPK-2 as a result of the activation of the p38 MAP kinase pathway. Phosphorylation and increased concentration of HSP27 has been implicated in actin polymerization and reorganization. HSP70 and HSP90 interact with unfolded proteins to prevent irreversible aggregation and catalyze the refolding of their substrates in an ATP- and co-chaperone-dependent manner. HSP70 has a broad range of substrates including newly synthesized and denatured proteins, while HSP90 tends to have a more limited subset of substrates, most of which are signaling molecules. HSP70 and HSP90 are also essential for the maturation and inactivation of nuclear hormones and other signaling molecules.
References
- Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Rev. Mol. Cell Biol. 10(8), 513–25.
- Horgan CP, McCaffrey MW (2009) The dynamic Rab11-FIPs. Soc. Trans. 37(Pt 5), 1032–6.
- Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. Med. Chem. 53(12), 4585–602.
- Lanneau D, Wettstein G, Bonniaud P, Garrido C (2010) Heat shock proteins: cell protection through protein triage. ScientificWorldJournal 10, 1543–52.
- Ghayour-Mobarhan M, Saber H, Ferns GA (2012) The potential role of heat shock protein 27 in cardiovascular disease. Chim. Acta 413(1-2), 15–24.
- Horgan CP, McCaffrey MW (2011) Rab GTPases and microtubule motors. Soc. Trans. 39(5), 1202–6.
- Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Rev. Mol. Cell Biol. 10(8), 513–25.
- Horgan CP, McCaffrey MW (2009) The dynamic Rab11-FIPs. Soc. Trans. 37(Pt 5), 1032–6.
- Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. Med. Chem. 53(12), 4585–602.
- Lanneau D, Wettstein G, Bonniaud P, Garrido C (2010) Heat shock proteins: cell protection through protein triage. ScientificWorldJournal 10, 1543–52.
- Ghayour-Mobarhan M, Saber H, Ferns GA (2012) The potential role of heat shock protein 27 in cardiovascular disease. Chim. Acta 413(1-2), 15–24.
- Horgan CP, McCaffrey MW (2011) Rab GTPases and microtubule motors. Soc. Trans. 39(5), 1202–6
– See more at: http://www.cellsignal.com/common/content/content.jsp?id=protein-folding#sthash.xAfeElH1.dpuf
Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds
Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Pharmacotherapy and Cell Activity, tagged Cancer - General, ginseng, Mayo Clinic on August 10, 2014| Leave a Comment »
Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds
Reporter: Larry H Bernstein, MD, FCAP
Ginseng fights fatigue in cancer patients, Mayo Clinic-led study finds Reply
15 JUN 2012
ROCHESTER, Minn. — High doses of the herb American ginseng (Panax quinquefolius) over two months reduced cancer-related fatigue in patients more effectively than a placebo, a Mayo Clinic-led study found. Sixty percent of patients studied had breast cancer. The findings are being presented at the American Society of Clinical Oncology’s annual meeting.
Researchers studied 340 patients who had completed cancer treatment or were being treated for cancer at one of 40 community medical centers. Each day, participants received a placebo or 2,000 milligrams of ginseng administered in capsules containing pure, ground American ginseng root.
“Off-the-shelf ginseng is sometimes processed using ethanol, which can give it estrogen-like properties that may be harmful to breast cancer patients,” says researcher Debra Barton, Ph.D., of the Mayo Clinic Cancer Center.
At four weeks, the pure ginseng provided only a slight improvement in fatigue symptoms. However, at eight weeks, ginseng offered cancer patients significant improvement in general exhaustion — feelings of being “pooped,” “worn out,” “fatigued,” “sluggish,” “run-down,” or “tired” — compared to the placebo group.
American ginseng (Photo credit: Wikipedia)
“After eight weeks, we saw a 20-point improvement in fatigue in cancer patients, measured on a 100-point, standardized fatigue scale,” Dr. Barton says. The herb had no apparent side effects, she says.
Ginseng has long been used in traditional Chinese medicine as a natural energy booster. Until this study, its effects had not been tested extensively against the debilitating fatigue that occurs in up to 90 percent of cancer patients. Fatigue in cancer patients has been linked to an increase in the immune system’s inflammatory cytokines as well as poorly regulated levels of the stress-hormone cortisol. Ginseng’s active ingredients, called ginsenosides, have been shown in animal studies to reduce cytokines related to inflammation and help regulate cortisol levels.
Dr. Barton’s next study will look closely at ginseng’s effects on the specific biomarkers for fatigue. “Cancer is a prolonged chronic stress experience and the effects can last 10 years beyond diagnosis and treatment,” she says. “If we can help the body be better modulated throughout treatment with the use of ginseng, we may be able to prevent severe long-term fatigue.”
Related articles
- Cancer Patients Fight Fatigue With Ginseng (medicalnewstoday.com)
- Ginseng supplement fights cancer-related fatigue(nyrnaturalnews.com)
- Ginseng as an energy booster: Mayo Clinic study shows benefits(blogs.vancouversun.com)
- Ginseng For Cancer Patients Says Mayo Clinic(medicalnewstoday.com)
- Ginseng Helps Patients Fight Cancer Fatigue (aarp.org)
SOURCE
Six Johns Hopkins Alzheimer’s Experts Discuss The Latest Discoveries
Posted in Academic Publishing, Alzheimer's Disease, Etiology, Innovations in Neurophysiology & Neuropsychology on August 5, 2014| Leave a Comment »
Six Johns Hopkins Alzheimer’s Experts Discuss The Latest Discoveries
Reporter: Aviva Lev-Ari, PhD, RN
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Special Offer from Johns Hopkins Health Alerts Six Alzheimer’s Experts Discuss The Latest Discoveries
Alzheimer’s Outlook 2014 Six leading experts provide the latest thinking on new and emerging approaches to the prevention, diagnosis and treatment of Alzheimer’s disease and other dementias * * * * * * * * * * * * * * * If you or a loved one has been diagnosed with Alzheimer’s disease or another memory disorder… Or if you are caring for someone with Alzheimer’s and are wondering if there’s a new drug or therapy in the pipeline that might help… Then it’s vitally important to stay on top of developments in the field — so you can ask your doctor the key questions — and discuss the critical issues that affect the management of the disease. To help you, we have just published Alzheimer’s Outlook 2014 — a valuable new resource that allows you to sit down with a group of preeminent physicians and listen in as they share their insights and ideas about the future course of Alzheimer’s disease — and provide a clear sense of what caregivers and patients can hope for. Alzheimer’s Outlook 2014 is part of a series of annual research reports written for concerned lay readers. It gives you special access to information you won’t find anywhere else on the future of Alzheimer’s research. What’s in the Alzheimer’s pipeline? In the past few years, researchers have made meaningful strides in the understanding of dementia prevention, diagnosis and treatment. Many important breakthroughs have come from the talented physicians and scientists working here at Johns Hopkins Medicine. In the pages of Alzheimer’s Outlook 2014 you’ll gain unprecedented access to the insights of Hopkins experts, as well as from colleagues at other renowned research centers. And there’s so much exciting information to report! Although we don’t yet have a drug to stop the disease progression, new techniques in molecular biology and genetics are providing remarkable insights into how and why Alzheimer’s begins, how it progresses and how it produces symptoms. Great progress has also been made in brain imaging and other biomarkers that might allow us to diagnose Alzheimer’s when no or minimal symptoms are present. Thanks to two new radiologic compounds researchers can now see the abnormal proteins in the brain and track the disease from one part of the brain to the next. Here’s a sample of other key highlights in Alzheimer’s Outlook 2014:
* * * * * * * * * * * * * * * As we mentioned, Alzheimer’s Outlook 2014 is part of a series of annual research updates on Alzheimer’s and related dementias. As a buyer of this year’s edition, you’ll be among the first to be notified when the 2015 edition is published next year. This is information so critical to being an informed patient that we want you to have it right away. We’ve created Alzheimer’s Outlook 2014 as an instant PDF download to ensure that you can start reading this material today. You can be sure your copy will contain up-to-the minute information to help stay on top of the latest developments. The information in Alzheimer’s Outlook 2014 is so crucial that we are making it available to you as a digital PDF download and a print version. You can be sure your copy will contain up-to-the minute information to help stay on top of the latest developments. Just click one of the order buttons below! Still not sure you’ll benefit from this Special Report? No problem. Alzheimer’s Outlook 2014 comes with a risk-free offer of satisfaction: if you’re not satisfied for any reason, simply contact Customer Service within 30 days for a prompt refund of your full purchase price of $29.95 So you risk nothing.
avivalev-ari@alum.berkeley.edu are receiving this email as part of your free subscription to Johns Hopkins Health Alerts. Should you wish to unsubscribe, please follow the instructions below. Help us be sure this email Health Alert isn’t filtered as spam. Adding our return address to your address book may “whitelist” us with your filter, helping future Health Alerts get to your inbox. Click here to be removed from all announcements concerning our publications. Need to contact us? Click here: http://www.johnshopkinshealthalerts.com/contact_us/ Johns Hopkins Health Alerts We value your privacy and will not give your email address to anyone. Click here to view our privacy policy. This information is not intended to substitute for the advice of a physician. Click here for additional information. Copyright © 2014 Remedy Health Media, LLC. 750 Third Avenue, 6th Floor, New York, NY 10017. All rights reserved. |
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Dementia does not cause Depression, Depression is independent of Demensia Biomarkers
Posted in Alzheimer's Disease, Etiology, Innovations in Neurophysiology & Neuropsychology, Pharmacotherapy and Cell Activity on July 30, 2014| Leave a Comment »
Dementia does not cause Depression, Depression is independent of Demensia Biomarkers
Reporter: Aviva Lev-Ari, PhD, RN
If the two Mental health conditions are independent, due to distinct etiologies —
What implications these research findings could have on Treatment of each of the diseases?
Depression in Elderly Not Related to Dementia Markers
Published: Jul 30, 2014
SOURCE
A New Risk Factor For Dementia: Depression Symptoms Linked To More Rapid Decline In Memory
Clinical-pathologic study of depressive symptoms and cognitive decline in old age
- Robert S. Wilson, PhD,
- Ana W. Capuano, PhD,
- Patricia A. Boyle, PhD,
- George M. Hoganson, MD,
- Loren P. Hizel, BA,
- Raj C. Shah, MD,
- Sukriti Nag, MD,
- Julie A. Schneider, MD,
- Steven E. Arnold, MD and
- David A. Bennett, MD
- Correspondence to Dr. Wilson: rwilson@rush.edu
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Neurology 10.1212/WNL.0000000000000715
- Abstract
- Full Text (PDF)
- Also available:
- Data Supplement
ABSTRACT
Objective: To clarify the relationship between depressive symptoms and the clinical and neuropathologic manifestations of dementia.
Methods: In a clinical-pathologic cohort study, 1,764 older persons without cognitive impairment at enrollment completed annual clinical evaluations for a mean of 7.8 years. The evaluations included assessment of depressive symptoms (10-item Center for Epidemiological Studies Depression Scale) and cognitive function (battery of 17 performance tests). A total of 582 individuals died during follow-up and underwent a uniform neuropathologic examination to quantify β-amyloid plaques and tau tangle density in multiple brain regions and identify neocortical Lewy bodies, hippocampal sclerosis, and gross and microscopic cerebral infarcts.
Results: Level of depressive symptoms slightly increased during follow-up. Incident mild cognitive impairment (52.2%) was associated with higher level of depressive symptoms before the diagnosis but not with change in symptoms after the diagnosis; incident dementia (17.9%) was associated with higher symptom level before dementia onset and with more rapid decline in symptoms after dementia onset. None of the neuropathologic markers was related to level of depressive symptoms or change in symptoms over time. In a mixed-effects model adjusted for the neuropathologic markers, higher level of depressive symptoms averaged over evaluations was associated with more rapid global cognitive decline, accounting for 4.4% of the variability in decline not attributable to the neuropathologic markers. Depressive symptoms did not modify the association of the neuropathologic markers with cognitive decline.
Conclusion: In old age, depressive symptoms have an association with cognitive decline that is independent of the neuropathologic hallmarks of dementia.
- Received February 6, 2014.
- Accepted in final form May 17, 2014.
- © 2014 American Academy of Neurology
SOURCE
http://www.neurology.org/content/early/2014/07/30/WNL.0000000000000715.short
Genes, proteomes, and their interaction
Posted in Alzheimer's Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Enzyme Induction, Evolutionary cognition, Gene Regulation, Genome Biology, Genomic Expression, Human Immune System in Health and in Disease, Ionic Transporters Na+, Metabolomics, Placenta, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Signaling, Technology Advance Assessment of, Transcriptomics, tagged genomics, Na-transporter, PARC, Proteomics, signaling pathways, thyroid hormone, transcrition on July 28, 2014| Leave a Comment »
Larry H. Bernstein, MD, FCAP, Author and Curator
http://pharmaceuticalintelligence.com/7/17/2014/Genes, proteomes, and their interaction
This is the third discussion of a several part series leading from the genome, to protein synthesis (1), posttranslational modification of proteins (2), examples of protein effects on metabolism and signaling pathways (3), and leading to disruption of signaling pathways in disease (4), and effects leading to mutagenesis.
1. A Primer on DNAand DNA Replication
2. Overview of translational medicine
3. Genes, proteomes, and their interaction
4. Regulation of somatic stem cell Function
5. Proteomics – The Pathway to Understanding and Decision-making in Medicine
6. Genomics, Proteomics and standards
7. Long Non-coding RNAs Can Encode Proteins After All
- http://pharmaceuticalintelligence.com/2014/06/29/long-non-coding-rnas-can-encode-proteins-after-all/
- 3:15 – 3:45, 2014, Laurie Boyer “Long non-coding RNAs: molecular regulators of cell fate”; http://pharmaceuticalintelligence.com/2014/06/04/koch-institute-for-integrative-cancer-research-mit-summer-symposium-2014-rna-biology-cancer-and-therapeutic-implications-june-13-2014-830am-430pm-kresge-auditorium-mit/
8. Proteins and cellular adaptation to stress
9. Loss of normal growth regulation
This discussion is the beginning of a diversion away from the routine discussion of a specific sequence and pairing of nucleotides in the classic model, to explore the interaction between proteins, or folded proteins and RNA or hidtones that reside in the nucleus and contribute to induction or inactivation of gene expression. The basic text document is rigid, inflexible, and resides in all cells. Yet, in bacteria, yeast, and eukaryotic cells, there are models of gene expression, and in eukaryotes, there is the development of expressed organ systems. These systems have similar proteins or enzymes that are functionally identical, but they have isoforms that bind with proteins, membranes, lipopolysaccharides, and lipoproteins – which has an impact on the catabolic and anabolic activity of the cells, and they are affected by oxidative stress, and they are often dependent on the energy of binding with metal ions,i.e., Mn, Cu, Cd, Zn,..,Fe, and in other cases anionic ligands, such as I, and they may transiently act through a nucleotide or influenced by a hormone.
This will be presented as a group of predetermined articles to follow:
1. Scientists discover a broad spectrum of alternatively spliced human protein variants within a well-studied family of genes.
2. Thyroid Hormone Key to Lipid Kinase Regulation
3. Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function
4 The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells
5. Nf k-beta signaling pathway
6. P181 cAMP-mediated Rac1 activation regulates the re-establishment of endothelial adherens junctions and barrier restoration during inflammation.
7. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
8. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia
9. Removing parts of shape-shifting protein explains how blood clots
1. Added Layers of Proteome Complexity
Scientists discover a broad spectrum of alternatively spliced human protein variants within a well-studied family of genes.
By Anna Azvolinsky | July 17, 2014
added layers of proteome
There may be more to the human proteome than previously thought. Some genes are known to have several different alternatively spliced protein variants, but the Scripps Research Institute’s Paul Schimmel and his colleagues have now uncovered almost 250 protein splice variants of an essential, evolutionarily conserved family of human genes. The results were published today (July 17) in Science.
Focusing on the 20-gene family of aminoacyl tRNA synthetases (AARSs), the team captured AARS transcripts from human tissues—some fetal, some adult—and showed that many of these messenger RNAs (mRNAs) were translated into proteins. Previous studies have identified several splice variants of these enzymes that have novel functions, but uncovering so many more variants was unexpected, Schimmel said. Most of these new protein products lack the catalytic domain but retain other AARS non-catalytic functional domains.
“The main point is that a vast new area of biology, previously missed, has been uncovered,” said Schimmel.
“This is an incredible study that fundamentally changes how we look at the protein-synthesis machinery,” Michael Ibba, a protein translation researcher at Ohio State University who was not involved in the work, told The Scientist in an e-mail. “The unexpected and potentially vast expanded functional networks that emerge from this study have the potential to influence virtually any aspect of cell growth.”
The team—including researchers at the Hong Kong University of Science and Technology, Stanford University, and aTyr Pharma, a San Diego-based biotech company that Schimmel co-founded—comprehensively captured and sequenced the AARS mRNAs from six human tissue types using high-throughput deep sequencing. While many of the transcripts were expressed in each of the tissues, there was also some tissue specificity.
Next, the team showed that a proportion of these transcripts, including those missing the catalytic domain, indeed resulted in stable protein products: 48 of these splice variants associated with polysomes. In vitro translation assays and the expression of more than 100 of these variants in cells confirmed that many of these variants could be made into stable protein products.
The AARS enzymes—of which there’s one for each of the 20 amino acids—bring together an amino acid with its appropriate transfer RNA (tRNA) molecule. This reaction allows a ribosome to add the amino acid to a growing peptide chain during protein translation. AARS enzymes can be found in all living organisms and are thought to be among the first proteins to have originated on Earth.
To understand whether these non-catalytic proteins had unique biological activities, the researchers expressed and purified recombinant AARS fragments, testing them in cell-based assays for proliferation, cell differentiation, and transcriptional regulation, among other phenotypes. “We screened through dozens of biological assays and found that these variants operate in many signaling pathways,” said Schimmel.
“This is an interesting finding and fits into the existing paradigm that, in many cases, a single gene is processed in various ways [in the cell] to have alternative functions,” said Steven Brenner, a computational genomics researcher at the University of California, Berkeley.
The team is now investigating the potentially unique roles of these protein splice variants in greater detail—in both human tissue as well as in model organisms. For example, it is not yet clear whether any of these variants directly bind tRNAs.
“I do think [these proteins] will play some biological roles,” said Tao Pan, who studies the functional roles of tRNAs at the University of Chicago. “I am very optimistic that interesting biological functions will come out of future studies on these variants.”
Brenner agreed. “There could be very different biological roles [for some of these proteins]. Biology is very creative that way, [it’s] able to generate highly diverse new functions using combinations of existing protein domains.” However, the low abundance of these variants is likely to constrain their potential cellular functions, he noted.
Because AARSs are among the oldest proteins, these ancient enzymes were likely subject to plenty of change over time, said Karin Musier-Forsyth, who studies protein translational at the Ohio State University. According to Musier-Forsyth, synthetases are already known to have non-translational functions and differential localizations. “Like the addition of post-translational modifications, splicing variation has evolved as another way to repurpose protein function,” she said.
One of the protein variants was able to stimulate skeletal muscle fiber formation ex vivo and upregulate genes involved in muscle cell differentiation and metabolism in primary human skeletal myoblasts. “This was really striking,” said Musier-Forsyth. “This suggests that, perhaps, peptides derived from these splice variants could be used as protein-based therapeutics for a variety of diseases.”
W.S. Lo et al., “Human tRNA synthetase catalytic nulls with diverse functions,” Science, http://dx.doi.org:/10.1126/science.1252943, 2014.
Tags tRNA, proteomics, protein synthesis and human proteome project
2. Thyroid Hormone Key to Lipid Kinase Regulation
Published: Jul 16, 2014 | Updated: Jul 17, 2014
By Salynn Boyles, Contributing Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and
Dorothy Caputo, MA, BSN, RN, Nurse Planner
Action Points
- Thyroid hormone is an essential regulator of human growth, brain maturation, and adult cognition and metabolism.
- This study provides evidence that cytoplasmic thyroid hormone signaling through phosphatidylinositol 3-kinase appears to be an essential mechanism underlying normal synaptic maturation and plasticity in the postnatal mouse hippocampus
Thyroid hormones are key for brain development and synaptic maturation, and researchers have identified a specific molecular mechanism for rapid lipid kinase activation by the thyroid hormone receptor beta (TR-beta) that involves a cytoplasmic complex of the gene.
Many effects of the thyroid hormone on mammalian cells in vitro have been shown to be mediated by the phosphatidylinositol 3-kinase (PI3K), but the molecular mechanism of PI3K regulation and its relevance to brain development have not been clear, according to David L. Armstrong, PhD, of the National Institute of Environmental Health and Development in Research Triangle, N.C., and colleagues.
They identified a specific molecular mechanism for rapid PI3 kinase activation by TR-beta which involves a cytoplasmic complex of TR-beta, the p85 regulatory subunit of PI3 kinase and the Src family kinase, Lyn, they wrote in Endocrinology.Armstrong’s co-authors are from Duke University and Loyola University in Chicago.
This complex provides a unique mechanism for integrating growth signals through thyroid hormone and receptor tyrosine kinases, they explained.
“Most everyone agrees that thyroid hormones are essential for brain development and synaptic maturation, but we didn’t know how exactly,” Armstrong told MedPage Today. “We show that nongenomic signaling in TR-beta through PI3 kinase is essential for one of its physiological actions.”
The Role of T3 Hormone
The recognition that many hormones regulate gene expression through receptor proteins that bind to DNA is a major biological discovery over the past 50 years, the researchers noted.
“More recently, it has become clear that in many cases the same hormones produce rapid effects on cell physiology though the same receptors signaling in the cytoplasm,” they wrote. “However, testing the relative importance of the genomic and nongenomic mechanisms in vivo has been prevented by the absence of specific molecular mechanisms for the nongenomic effects that could be blocked by mutation of the receptor without disrupting its direct effects on gene expression.”
The thyroid hormone T3 has been shown to be a regulator of many physiological effects, including human growth, brain maturation, and adult cognition and metabolism.
Many of these effects have been found to be mediated through the regulation of gene expression by zinc-finger nuclear receptor proteins that are encoded by the THRA and THRB genes. But many in vitro effects of T3 are too rapid to be explained by transcriptional regulation, Armstrong and colleagues noted.
In earlier work, they identified PI3 kinase as a key player in these rapid effects. Like thyroid hormone, PI3 kinase activity has been identified as essential for growth, metabolism, and brain development.
PI3 kinase is regulated primarily by receptor tyrosine kinases, and an integrin receptor has been identified that mediates some of the PI3 kinase-dependent effects of thyroxine (T4), the widely circulated precursor of T3.
Both TR-alpha and TR-beta have also been reported to associate with PI3 kinase and stimulate its activity in many cell types. In a 2006 study in the Proceedings of the National Academy of Sciences, Armstrong and colleagues demonstrated that TRis required to reconstitute T3 and PI3 kinase-dependent regulation of Kv11.1 channels in cell-free membrane patches from Chinese hamster ovary (CHO) cells.
Based on that research, they concluded that TR-beta signaling through PI3K “provides a molecular explanation for the essential role of thyroid hormone in human brain development and adult lipid metabolism.”
Measuring PIP3 Production
In the newly reported series of experiments, the researchers used fluorescent PIP3 indicator to directly measure PIP3 production in response to thyroid hormone on the same time scale as the electrophysiological measurements in the CHO cells expressing recombinant human thyroid hormone receptors.
The research revealed that, in the absence of hormone, the nuclear receptor TR-beta forms a cytoplasmic complex with the p85 subunit of PI3 kinase and the Src family tyrosine kinase, Lyn, which depends on two canonical phosphotyrosine motifs in the second zinc finger of TR that are not conserved in TR-beta
“When hormone is added, [TR-beta] dissociates and moves to the nucleus, and PIP3production goes up rapidly,” the researchers wrote. “Mutating either tyrosine to a phenylalanine prevents rapid signaling through PI3 kinase but does not prevent hormone-dependent transcription of genes with a thyroid hormone response element.”
“It is only when you have both thyroid hormone and phosphotyrosine signaling that you get maximal stimulation of PI3 kinase,” Armstrong said, adding that the novel methodology of the study, which involved serum from thyroidectomized animals, led to the finding.
These experiments led to in vivo research to test the physiological relevance of thyroid hormone signaling through PI3 kinase for brain development in a novel mouse line created by the researchers.
“We reasoned that blocking binding of TR-beta to p85 by mutating Y171 might eliminate any dominant negative effect of the mutant, in much the same way that receptor knockdown proved much less deleterious to the organism than hormone withdrawal, presumably because many of the effects of the receptor on gene expression are mediated by binding of the unliganded receptor,” they wrote.
They created a novel mouse line with a targeted mutation knocked into the THRB gene to substitute phenylalanine for tyrosine at residue 147 of TR-beta-1, which prevents Lyn binding to the mutant receptor.
They confirmed that the mutation did not alter total circulating levels of thyroxine (T4) or T3 by mass spectrometry of serum samples from 4-month-old mice.
“When the rapid signaling mechanism was blocked chronically throughout development in mice by a targeted point mutation in both alleles of THRB, circulating hormone levels, TR-betaexpression, and direct gene regulation by TR-beta in the brain and liver were all unaffected,” the researchers wrote. “The mutation did significantly impair maturation and plasticity of the Schaffer collateral synapses on CA1 pyramidal neurons in the postnatal hippocampus. Thus, phosphotyrosine-dependent association of TR-betawith PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases.”
A Novel Finding
The finding that thyroid hormone signaling through PI3 kinase appears to be an essential mechanism underlying normal synaptic maturation and plasticity in the postnatal mouse hippocampus is novel.
The researchers noted that they could not formally exclude some more subtle effects of the mutation on the regulation of an unknown gene that plays as central a role in synaptic development as PI3K, but the added that “our results do categorically rule out a role for other thyroid hormone receptors in this particular aspect of synaptic maturation in the mouse hippocampus.
“In either case, given the importance of thyroid hormone signaling for human brain development and adult metabolism, future studies will need to investigate whether PI3 kinase stimulation by thyroid hormone is also susceptible to disruption by environmental toxicants,” they wrote.
Armstrong also pointed out that the tyrosine motifs in TR-beta, which were shown to be essential for signaling through PI3 kinase, are present in all mammals, but not in other species with known genome data, with the exception of the gecko and the axolotl (Mexican salamander).
“Mammals evolved from reptiles, and the thinking is that they survived by adopting a nocturnal niche,” he said. “This is exactly what thyroid hormone does, so it may be that this mutation contributed to the (evolutionary) success of mammals.”
Primary source: Endocrinology
Source reference: Martin NP, et al “A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TR beta, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo”
Endocrinology 2014; http://dx.doi.org:/10.1210/en.2013-2058.
3. Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function.
Lianjun Zhang, Benjamin O Tschumi, Stéphanie Corgnac, Markus A Rüegg,Michael N Hall, Jean-Pierre Mach, Pedro Romero, Alena Donda
Journal of immunology (Baltimore, Md. : 1950) 07/2014; http://dx.doi.org:/10.4049/jimmunol.1400769
Source: PubMed
ABSTRACT Invariant NKT (iNKT) cells play critical roles in bridging innate and adaptive immunity. The Raptor containing mTOR complex 1 (mTORC1) has been well documented to control peripheral CD4 or CD8 T cell effector or memory differentiation. However, the role of mTORC1 in iNKT cell development and function remains largely unknown. By using mice with T cell-restricted deletion of Raptor, we show that mTORC1 is selectively required for iNKT but not for conventional T cell development. Indeed, Raptor-deficient iNKT cells are mostly blocked at thymic stage 1-2, resulting in a dramatic decrease of terminal differentiation into stage 3 and severe reduction of peripheral iNKT cells. Moreover, residual iNKT cells in Raptor knockout mice are impaired in their rapid cytokine production upon αGalcer challenge. Bone marrow chimera studies demonstrate that mTORC1 controls iNKT differentiation in a cell-intrinsic manner. Collectively, our data provide the genetic evidence that iNKT cell development and effector functions are under the control of mTORC1 signaling.
4. PARC
The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells
Vivian Gama1,2, Vijay Swahari1,2, Johanna Schafer1*, Adam J. Kole2, Allyson Evans2, Yolanda Huang2, Anna Cliffe1,2, Brian Golitz3,4, Noah Sciaky3,4, Xin-Hai Pei5,6, Yue Xiong5,6, and Mohanish Deshmukh1,2,5
1 Neuroscience Center, 2 Department of Cell Biology and Physiology, 3 UNC RNAi Screening Facility,4 Department of Pharmacology, 5 Lineberger Comprehensive Cancer Center, 6 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.* Present address: Vanderbilt University, Nashville, TN 37232, USA. Present address: Cell Press, Cambridge, MA 02139, USA. Present address: Department of Anesthesiology, Columbia University Medical Center, New York, NY 10032, USA.
Abstract: The ability to withstand mitochondrial damage is especially critical for the survival of postmitotic cells, such as neurons. Likewise, cancer cells can also survive mitochondrial stress. We found that cytochrome c (Cyt c), which induces apoptosis upon its release from damaged mitochondria, is targeted for proteasome-mediated degradation in mouse neurons, cardiomyocytes, and myotubes and in human glioma and neuroblastoma cells, but not in proliferating human fibroblasts. In mouse neurons, apoptotic protease-activating factor 1 (Apaf-1) prevented the proteasome-dependent degradation of Cyt c in response to induced mitochondrial stress. An RNA interference screen in U-87 MG glioma cells identified p53-associated Parkin-like cytoplasmic protein (PARC, also known as CUL9) as an E3 ligase that targets Cyt c for degradation. The abundance of PARC positively correlated with differentiation in mouse neurons, and overexpression of PARC reduced the abundance of mitochondrially-released cytosolic Cyt c in various cancer cell lines and in mouse embryonic fibroblasts. Conversely, neurons from Parc-deficient mice had increased sensitivity to mitochondrial damage, and neuroblastoma or glioma cells in which PARC or ubiquitin was knocked down had increased abundance of mitochondrially-released cytosolic Cyt c and decreased viability in response to stress. These findings suggest that PARC-mediated ubiquitination and degradation of Cyt c is a strategy engaged by both neurons and cancer cells to prevent apoptosis during conditions of mitochondrial stress.
Sci. Signal., 15 July 2014 Vol. 7, Issue 334, p. ra67
http://dx.doi.org:/10.1126/scisignal.2005309
Citation: V. Gama, V. Swahari, J. Schafer, A. J. Kole, A. Evans, Y. Huang, A. Cliffe, B. Golitz, N. Sciaky, X.-H. Pei, Y. Xiong, M. Deshmukh, The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells. Sci. Signal. 7, ra67 (2014).
Killing the Killer: PARC/CUL9 Promotes Cell Survival by Destroying Cytochrome c
Jonathan Lopez and Stephen W. G. Tait*
Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Abstract: Balanced amounts of apoptotic cell death are essential for health; its deregulation plays key roles in neurodegeneration, autoimmunity, and cancer. Mitochondria orchestrate apoptosis through a process called mitochondrial outer-membrane permeabilization (MOMP). After MOMP, mitochondrial cytochrome c is released into the cytoplasm, where it binds the adaptor molecule APAF1, triggering caspase protease activation and cell death. In this issue of Science Signaling, Deshmukh and colleagues define a new survival mechanism downstream of mitochondrial permeabilization. Specifically, they identify proteasomal degradation of cytochrome c as a major determinant of cell survival. In an unbiased approach, PARC (also known as CUL9) was found to be the ubiquitin ligase responsible for the ubiquitination and proteasomal degradation of cytochrome c. The consequences of this survival process may be double-edged because both cancer cells and postmitotic cells use PARC/CUL9–mediated cytochrome c degradation to ensure cell survival. Ultimately, differential targeting of this process may promote survival of postmitotic tissue or enhance tumor-specific killing.
Citation: J. Lopez, S. W. G. Tait, Killing the Killer: PARC/CUL9 Promotes Cell Survival by Destroying Cytochrome c. Sci. Signal. 7, pe17 (2014).
Sci. Signal., 15 July 2014 Vol. 7, Issue 334, p. pe17
http://dx.doi.org:/10.1126/scisignal.2005619
4. The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters
Dario R. Alessi1, Jinwei Zhang1, Arjun Khanna2, Thomas Hochdörfer1, Yuze Shang3, and Kristopher T. Kahle2,3*
1 MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
2 Department of Neurosurgery, Massachusetts General Hospital, and Harvard Medical School, 3 Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA 02115, USA.
Abstract: The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress–responsive kinase 1). The WNK family senses changes in intracellular Cl– concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na+), potassium (K+), and chloride (Cl–) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl–-importing, Na+-driven CCCs or inhibit the Cl–-extruding, K+-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK-SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K+ secretion to lower blood pressure while maintaining serum K+. In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl–extrusion and promote -aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K+-sparing blood pressure–lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism.
Citation: D. R. Alessi, J. Zhang, A. Khanna, T. Hochdörfer, Y. Shang, K. T. Kahle, The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters. Sci. Signal. 7, re3 (2014).
Sci. Signal., 15 July 2014 Vol. 7, Issue 334, p. re3
http://dx.doi.org:/10.1126/scisignal.2005365
5. Nf k-beta signaling pathway
Cracking the NF-B Code
Karen E. Tkach, Jennifer E. Oyler, and Grégoire Altan-Bonnet*
ImmunoDynamics Group, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract: The discovery of feedback loops between signaling and gene expression is ushering in new quantitative models of cellular regulation. In a recent issue of Science Signaling, Sung et al. showed how positive feedback downstream of nuclear factor B (NF-B) signaling enhances the capacity of macrophages to scale their antimicrobial responses to the dose of pathogen-associated molecular cues. This finding stemmed from analysis of cell-to-cell variability and computational modeling of time integration between signaling and transcriptional responses. Ultimately, such quantitative approaches challenge the oft-assumed time separation of “fast” signal transduction followed by “slow” gene expression, and they provide a better understanding of complex biological regulation over long time scales.
Citation: K. E. Tkach, J. E. Oyler, G. Altan-Bonnet, Cracking the NF-B Code. Sci. Signal. 7, pe5 (2014).
Sci. Signal., 18 February 2014 Vol. 7, Issue 313, p. pe5
http://dx.doi.org:/10.1126/scisignal.2005108
Switching of the Relative Dominance Between Feedback Mechanisms in Lipopolysaccharide-Induced Nfk-B Signaling
Myong-Hee Sung1*, Ning Li2, Qizong Lao1, Rachel A. Gottschalk2, Gordon L. Hager1*, and Iain D. C. Fraser2*
1 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, 2 Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract: A fundamental goal in biology is to gain a quantitative understanding of how appropriate cell responses are achieved amid conflicting signals that work in parallel. Through live, single-cell imaging, we monitored both the dynamics of nuclear factor B (NF-B) signaling and inflammatory cytokine transcription in macrophages exposed to the bacterial product lipopolysaccharide (LPS). Our analysis revealed a previously uncharacterized positive feedback loop involving induction of the expression of Rela, which encodes the RelA (p65) NF-B subunit. This positive feedback loop rewired the regulatory network when cells were exposed to LPS above a distinct concentration. Paradoxically, this rewiring of NF-B signaling in macrophages (a myeloid cell type) required the transcription factor Ikaros, which promotes the development of lymphoid cells. Mathematical modeling and experimental validation showed that the RelA positive feedback overcame existing negative feedback loops and enabled cells to discriminate between different concentrations of LPS to mount an effective innate immune response only at higher concentrations. We suggest that this switching in the relative dominance of feedback loops (“feedback dominance switching”) may be a general mechanism in immune cells to integrate opposing feedback on a key transcriptional regulator and to set a response threshold for the host.
Citation: M.-H. Sung, N. Li, Q. Lao, R. A. Gottschalk, G. L. Hager, I. D. C. Fraser, Switching of the Relative Dominance Between Feedback Mechanisms in Lipopolysaccharide-Induced NF-B Signaling. Sci. Signal. 7, ra6 (2014).
Sci. Signal., 14 January 2014 Vol. 7, Issue 308, p. ra6
http://dx.doi.org:/10.1126/scisignal.2004764
Drug development in the Alzheimer’s field has been riddled with failures, and most research efforts have focused on pinpointing genetic and environmental factors responsible for causing or accelerating the progression of the disease.
Now, researchers from Montreal’s Douglas Mental Health Institute and McGill University have identified a relatively frequent genetic variant that may provide protection against the devastating neurodegenerative disease.
“We found that specific genetic variants in a gene called HMG CoA reductase which normally regulates cholesterol production and mobilization in the brain can interfere with, and delay the onset of Alzheimer’s disease by nearly four years. This is an exciting breakthrough in a field where successes have been scarce these past few years,” said Dr. Judes Poirier, whose previous research led to the discovery that a genetic variant was formally associated with the common form of Alzheimer’s disease.
This variant may explain why some people who are carriers of predisposing genetic factors for the common form of Alzheimer’s do not develop the disease, living long lives without memory problems until their nineties.
6. P181 cAMP-mediated Rac1 activation regulates the re-establishment of endothelial adherens junctions and barrier restoration during inflammation.
M Aslam, H Nef, C Troidl, R Schulz, T Noll, C Hamm, D Guenduez
Cardiovascular research 07/2014; 103(suppl 1):S32.
http://dx.doi.org:/10.1093/cvr/cvu082.117
Source: PubMed
ABSTRACT Inflammatory mediators like thrombin and TNFα disrupt endothelial junctions and barrier integrity, leading to edema formation. This increase in endothelial permeability is followed by slow restoration of the endothelial barrier, which is critical for the maintenance of basal endothelial permeability. However, the molecular mechanism of recovery of the endothelial barrier in response to inflammatory mediators has not yet been well delineated. The aim of the present study was to explore the mechanism of this barrier restoration. Specific emphasis was given to the role of Rac1 GTPase activation, which is an important regulator of endothelial adherens junction (AJ) integrity.
7. Thalidomide
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Eric S. Fischer, Kerstin Böhm, John R. Lydeard, Haidi Yang, Michael B. Stadler, et al.
Nature (2014) http://dx.doi.org:/10.1038/nature13527
In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4CRBN) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4CRBN. Here we present crystal structures of the DDB1–CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4CRBN and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.
Figure 1: The overall structure of the DDB1–CRBN complex.
http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature13527-f1.jpg
a, Cartoon representation of the structure of the complex of human DDB1, G. gallus CRBN and thalidomide: DDB1, highlighting the domains BPA (red), BPB (magenta), BPC (orange) and DDB1-CTD (grey); G. gallus CRBN, highlighting the domain…
Figure 2: IMiD binding to CRBN.
http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature13527-f2.jpg
a, Chemical structure of lenalidomide. b, Chemical structure of pomalidomide. c, Sketch of thalidomide and its interactions with G. gallus CRBN. Hydrogen bonds are shown as dashed lines, and hydrophobic interactions are indicated as gr
Figure 3: CRBN is a substrate receptor in the ligase CRL4CRBN.
http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature13527-f3.jpg
a, Architecture of the CRL4DDB2 complex bound to DNA (PDB ID 4A0K). b, Model of CRL4CRBN bound to thalidomide. c, Firefly luciferase (Fluc) to Renillaluciferase (Rluc) ratios (Fluc:Rluc) of IKZF1-reporter-plasmid-transfected HEK 293T…
Figure 5: Molecular model of IMiD function.
http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature13527-f5.jpg
a, Thalidomide binds to CRBN at the canonical substrate-binding site. b, The potent anti-myeloma drug thalidomide and its derivatives lenalidomide and pomalidomide occupy the same site but with different solvent-exposed moieties. c, Bi…
8. Preeclampsia of pregnancyand protein misfolding
Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia
Irina A. Buhimschi1,2,*, Unzila A. Nayeri2, Guomao Zhao1, Lydia L. Shook2, Anna Pensalfini3, et al.
1Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, 4Depart of ObGyn, The Ohio State University College of Medicine, Columbus, OH
2Depart of ObGyn and Reproductive Sciences, Yale University School of Medicine, New Haven, CT
3Center for Dementia Research, Nathan Kline Institute for Psychiatric Research and Department of Psychiatry, New York University School of Medicine, New York, NY
5Depart of ObGyn and Reproductive Sciences, University of Vermont College of Medicine, Burlington, VT .
6Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92617, USA.
7Department of Biochemistry and Experimental Biochemistry Unit, King Abdulaziz Univ, Jeddah , Saudi Arabia.
Preeclampsia is a pregnancy-specific disorder of unknown etiology and a leading contributor to maternal and perinatal morbidity and mortality worldwide. Because there is no cure other than delivery, preeclampsia is the leading cause of iatrogenic preterm birth. We show that preeclampsia shares pathophysiologic features with recognized protein misfolding disorders. These features include urine congophilia (affinity for the amyloidophilic dye Congo red), affinity for conformational state–dependent antibodies, and dysregulation of prototype proteolytic enzymes involved in amyloid precursor protein (APP) processing. Assessment of global protein misfolding load in pregnancy based on urine congophilia (Congo red dot test) carries diagnostic and prognostic potential for preeclampsia. We used conformational state–dependent antibodies to demonstrate the presence of generic supramolecular assemblies (prefibrillar oligomers and annular protofibrils), which vary in quantitative and qualitative representation with preeclampsia severity. In the first attempt to characterize the preeclampsia misfoldome, we report that the urine congophilic material includes proteoforms of ceruloplasmin, immunoglobulin free light chains, SERPINA1, albumin, interferon-inducible protein 6-16, and Alzheimer’s β-amyloid. The human placenta abundantly expresses APP along with prototype APP-processing enzymes, of which the α-secretase ADAM10, the β-secretases BACE1 and BACE2, and the γ-secretase presenilin-1 were all up-regulated in preeclampsia. The presence of β-amyloid aggregates in placentas of women with preeclampsia and fetal growth restriction further supports the notion that this condition should join the growing list of protein conformational disorders. If these aggregates play a pathophysiologic role, our findings may lead to treatment for preeclampsia.
Citation: I. A. Buhimschi, U. A. Nayeri, G. Zhao, L. L. Shook, A. Pensalfini, E. F. Funai, I. M. Bernstein, C. G. Glabe, C. S. Buhimschi,Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Sci. Transl. Med. 6, 245ra92 (2014).
9. Blood Clotting
Removing parts of shape-shifting protein explains how blood clots
prothrombin (FII)
Using x-ray crystallography, SLU researchers published the first image of the important blood-clotting protein prothrombin (coagulation factor II). The protein’s flexible structure is key to the development of blood-clotting.In results recently published in Proceedings of the National Academy of Sciences (PNAS), Saint Louis University scientists have discovered that removal of disordered sections of a protein’s structure reveals the molecular mechanism of a key reaction that initiates blood clotting.
Enrico Di Cera, M.D., chair of the Edward A. Doisy department of biochemistry and molecular biology at Saint Louis University, studies thrombin, a key vitamin K-dependent blood-clotting protein, and its inactive precursor prothrombin (or coagulation factor II).
“Prothrombin is essential for life and is the most important clotting factor,” Di Cera said. “We are proud to report that our lab here at SLU has finally succeeded in crystallizing prothrombin for the first time.”
Blood-clotting has long ensured our survival, stopping blood loss after an injury. However, when triggered in the wrong circumstances, clotting can lead to debilitating or fatal conditions such as a heart attack, stroke or deep vein thrombosis.
Before thrombin becomes active, it circulates throughout the blood in the inactive (zymogen) form called prothrombin. When the active enzyme is needed (after a vascular injury, for example), the coagulation cascade is initiated and prothrombin is converted into the active enzyme thrombin that causes blood to clot.
X-ray crystallography is one tool in scientists’ toolbox for understanding processes at the molecular level. It offers a way to obtain a “snap shot” of a protein’s structure.
In this technique, scientists grow crystals of the protein they want to study, shoot x-rays at them and record data about the way the rays are scattered by crystals. Then they use computer programs to create an image of the protein based on that data.
Once scientists can visualize the three dimensional structure of a molecule, they can begin to piece together the way in which the protein functions and interacts with other molecules in the body, or with drugs.
Last year, Di Cera and colleagues published the first structure of prothrombin. This first structure lacked a domain responsible for interaction with membranes and certain other sections were not detected by x-ray analysis. Though the scientists were able to crystallize the protein, there were disordered regions in the structure that they could not see.
Within prothrombin there are two kringle domains (looped sections of a protein named after the Scandinavian pastry) connected by a “linker” region that intrigued the SLU investigators because of its intrinsic disorder.
“We deleted this linker and crystals grew in a few days instead of months, revealing for the first time the full architecture of prothrombin,” Di Cera said.
In addition to this remarkable discovery, Di Cera and colleagues found that the deleted version of prothrombin is activated to thrombin much faster than the intact prothrombin. The structure without the disordered linker is in fact optimized for conversion to thrombin and reveals key information on the mechanism of prothrombin activation.
For over four decades, scientists have tried to crystallize prothrombin but without success.
“It took us almost two years to discover that the disordered linker was the key,” Di Cera said. “Finally, prothrombin revealed its secrets and with that the molecular mechanism of a key reaction of blood clotting finally becomes amenable to rational drug design for therapeutic intervention.”
SLU researchers Nicola Pozzi, Ph.D., Zhiwei Chen, Leslie Pelc and Daniel Shropshire also are authors on the paper.
Diagnostic Approach to Neurodegenerative Disorders: Biomarkers Overview
Posted in Academic Publishing, Alzheimer's Disease, Biomarkers & Medical Diagnostics, Etiology, Immunodiagnostics, Innovations in Neurophysiology & Neuropsychology, Pharmacotherapy and Cell Activity on July 16, 2014| Leave a Comment »
Diagnostic Approach to Neurodegenerative Disorders: Biomarkers Overview
Reporter: Aviva Lev-Ari, PhD, RN
ANNOUNCEMENT by Cambridge Healthtech Institute
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Biomarkers: Discovery and Development for a Diagnostic Approach to Neurodegenerative Disorders – Overview
Available Mid-July!
Biomarkers: Discovery and Development for a Diagnostic Approach to Neurodegenerative Disorders has a focus in biomarkers for neurodegenerative diseases and diagnostic applications in development. Biomarkers have been a heavily studied topic of interest, and recently on the rise is the interest in neurodegenerative disorders. Although there are many techniques used to track neurodegenerative disease progression, this report will primarily focus on blood-based and cerebrospinal fluid-based biomarkers. In addition to covering background information, this report will highlight several technologies that have been developed for employing the use of biomarkers for neurodegenerative disease detection, analysis and therapeutic development. Including substantial background information, illustrated with graphics and figures, this report captures market growth of biomarkers, advantages, disadvantages, and validation techniques.
Three neurodegenerative disorders that are heavily focused on in this report include: Alzheimer’s Disease/Mild Cognitive Impairment, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. Part II of the report will include all three of these disorders, highlighting specifics including background, history, and development of the disease. Deeper into the chapters, the report will unfold biomarkers under investigation, genetic targets, and an analysis of multiple studies investigating these elements.
Experts interviewed in these chapters include:
- Dr. Jens Wendland, Head of Neuroscience Genetics, Precision Medicine, PharmaTherapeutics, Pfizer Worldwide R&D
- Dr. Howard J. Federoff, Executive Vice President for Health Sciences, Georgetown University
- Dr. Andrew West, Associate Professor of Neurology and Neurobiology and Co-Director, Center for Neurodegeneration and Experimental Therapeutics
- Dr. Merit Ester Cudkowicz, Chief of Neurology at Massachusetts General Hospital
Part III of the report makes a shift from neurobiomarkers to neurodiagnostics. This section highlights several diagnostics in play and in the making from a number of companies, identifying company strategies, research underway, hypotheses, and institution goals. Elite researchers and companies highlighted in this part include:
- Dr. Xuemei Huang, Professor and Vice Chair, Department of Neurology; Professor of Neurosurgery, Radiology, Pharmacology, and Kinesiology Director; Hershey Brain Analysis Research Laboratory for Neurodegenerative Disorders, Penn State University-Milton, S. Hershey Medical Center Department of Neurology
- Dr. Andreas Jeromin, CSO and President of Atlantic Biomarkers
- Julien Bradley, Senior Director, Sales & Marketing, Quanterix
- Dr. Scott Marshall, Head of Bioanalytics, and Dr. Jared Kohler, Head of Biomarker Statistics, BioStat Solutions, Inc.
Further analysis appears in Part IV. This section includes a survey exclusively conducted for this report. With over 30 figures and graphics and an in depth analysis, this part features insight into targets under investigation, challenges, advantages, and desired features of future diagnostic applications. Furthermore, the survey covers more than just the featured neurodegenerative disorders in this report, expanding to Multiple Sclerosis and Huntington’s Disease.
Furthermore, Insight Pharma Reports also put together a generous amount of data compiling clinical trial information and pipeline data related to Alzheimer’s Disease, Parkinson’s Disease and Amyotrophic Lateral Sclerosis. This is the fifth and final part of this report and it contains the most current information in the aforementioned disease areas. Such information was provided by CenterWatch and Biotechgate Global Database.
SOURCE
http://www.insightpharmareports.com/neurobiomarkers-and-diagnostics-report
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Date: Wed, 16 Jul 2014 15:20:07 -0400
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Subject: Biomarkers and Neurodegenerative Disorders
MIND AND MEMORY: BIOLOGICAL AND DIGITAL – 2014 Dan David Prize Symposium
Posted in Alzheimer's Disease, Etiology, Genome Biology, Genomic Testing: Methodology for Diagnosis, Innovations in Neurophysiology & Neuropsychology, Interviews with Scientific Leaders, Medical and Population Genetics, Pharmacotherapy and Cell Activity, Scientific & Biotech Conferences: Press Coverage, Scientist: Career considerations, tagged MIND AND MEMORY: BIOLOGICAL AND DIGITAL on June 18, 2014| Leave a Comment »
MIND AND MEMORY: BIOLOGICAL AND DIGITAL – 2014 Dan David Prize Symposium
Reporter: Aviva Lev-Ari, PhD, RN
Article ID #145: MIND AND MEMORY: BIOLOGICAL AND DIGITAL – 2014 Dan David Prize Symposium. Published on 6/18/2014
WordCloud Image Produced by Adam Tubman
View VIDEO for this Symposium, link provided following the Symposium Agenda
Mind and Memory: Biological and Digital
with the 2014 Dan David Prize Laureates in the Present and Future Time Dimensions
Prof. John A. Hardy, Prof. Peter St. George-Hyslop,
Prof. Brenda Milner and
Prof. Marvin Minsky
The symposium will take place on Tuesday, May 20, 2014 at 8:30 a.m.
The Miriam and Adolfo Smolarz Auditorium, Tel Aviv University
Moderators:
Prof. Uri Ashery
Sagol School of Neuroscience
Tel Aviv University
Prof. Nachum Dershowitz
The Blavatnik School of Computer Science
Tel Aviv University
8:30 Gathering
9:00 Greetings
Prof. Yoav Henis
Vice President, Research and Development
Tel Aviv University
HE Mr. Matthew Gould
The British Ambassador to Israel
9:15 Prof. John A. Hardy
University College London, UK
“Whole Genome Analysis and the Pathogenesis of Alzheimer’s Disease”
9:55 Prof. Peter St. George-Hyslop
University of Toronto, Canada
University of Cambridge, UK
“Biochemical Genetics of Alzheimer’s Disease”
10:35 Prof. Danny Michaelson
Sagol School of Neuroscience
and Department of Neurobiology
Tel Aviv University
“Translational Alzheimer’s Disease Research at Tel Aviv University”
10:50 Coffee Break
11:30 Prof. Brenda Milner
McGill University, Canada
“Temporal Lobes and Memory: Looking Back and Looking Forward”
12:10 Dr. Segev Barak
The School of Psychological Sciences
and Sagol School of Neuroscience
Tel Aviv University
“Preventing Relapse in Alcoholism by Memory Erasure:
Neurobiological Mechanisms of Memory Plasticity”
12:25 Lunch Break and Poster Viewing
14:15 Prof. Yael Hanein
School of Electrical Engineering
and Sagol School of Neuroscience
Tel Aviv University
“How Many Neurons Does It Take to Change a Light Bulb?”
14:30 Prof. Lior Wolf
The Blavatnik School of Computer Science
Tel Aviv University
“DeepFace: Closing the Gap to Human-Level Performance in Face Verification”
14:45 Prof. Nathan Intrator
The Blavatnik School of Computer Science
and Sagol School of Neuroscience
Tel Aviv University
“Brain Inspired Computation in the 21st Century”
15:00 Prof. Marvin Minsky
Massachusetts Institute of Technology, USA
“Future Theories of Mind”
15:40 Concluding Remarks
VIEW VIDEO
http://dandavidprize.org/media-events/symposia/2014/694-mind-and-memory-biological-and-digital
Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.
Posted in Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Curation, Diabetes Mellitus, FDA Regulatory Affairs, Health Economics and Outcomes Research, Healthcare costs and reimbursement, HealthCare IT, Interviews with Scientific Leaders, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Personal Health Applications: Tech Innovations serves HealhCare, Translational Effectiveness, tagged #mhealth, #mobilehealth, Cancer - General, cancer patient management, Chemotherapy, compliance issues, Conditions and Diseases, health, Health Information Technology, HIIPA compliance, mobile applications, oncology, oral chemotherapy, patient adherence on June 17, 2014| Leave a Comment »
Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.
Reporter: Stephen J. Williams, PhD
Article ID #144: Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification. Published on 6/17/2014
WordCloud Image Produced by Adam Tubman
A report on how gamification mobile applications, like CyberDoctor’s PatientPartner, may improve patient adherence to oral chemotherapy.
(includes interviews with CyberDoctor’s CEO Akhila Satish and various oncologists)
Writer/Curator: Stephen J. Williams, Ph.D.
UPDATE 5/15/2019
Please see below for an UPDATE on this post including results from the poll conducted here on the value of a gamification strategy for oral chemotherapy patient adherence as well as a paper describing a well designed development of an application specifically to address this clinical problem.
Studies have pointed to a growing need to monitor and improve medical adherence, especially with outpatient prescription drugs across many diseases, including cancer.
The trend to develop oral chemotherapies, so patients can take their medications in the convenience of their home, has introduced produced a unique problem concerning cancer patient-medication adherence. Traditionally, chemotherapies were administered by a parental (for example intravenous) route by clinic staff, however, as noted by Jennifer M Gangloff in her article Troubling Trend: Medication Adherence:
with the trend of cancer patients taking their oral medication at home, the burden of adherence has shifted from clinicians to the patients and their families.
A few highlights from Jennifer Gangloff’s article highlight the degree and scope of the problem:
- There is a wide range of adherence for oral chemo– as low as 16% up to 100% adherence rates have been seen in multiple studies
- High cost in lives and money: estimates in US of 125,000 deaths and $300 billion in healthcare costs due to nonadherence to oral anticancer medications
- Factors not related to the patient can contribute to nonadherence including lack of information provided by the healthcare system and socioeconomic factors
- Numerous methods to improve adherence issues (hospital informative seminars, talking pill bottles, reminder phone calls etc.) have met with mixed results.
A review by Steve D`Amato of published literature also highlights the extent of problems with highly variable adherence rates including
- 17-27% for hematologic malignancies
- 53-98% for breast cancer
- 97% for ovarian cancer
More strikingly, patient adherence rates can drastically decline over treatment, with one study showing an adherence rate drop from 87% to 50% over 4 years of adjuvant tamoxifen therapy.
Tackling The Oral Chemotherapy-Patient Adherence Problem
Documented factors leading to non-adherence to oral oncology medications include
- Patient feels better so stop taking the drug
- Patient feels worse so stops taking the drug
- Confusing and complicated dosing regimen
- Inability to afford medications
- Poor provider-patient relationships
- Adverse effects of medication
- Cognitive impairment (“chemo fog”; mental impairment due to chemotherapy
- Inadequate education/instruction of discharge
There are many examples of each reason why a patient stopped taking medication. One patient was prescribed capecitabine for her metastatic breast cancer and, upon feeling nausea, started to use antacids, which precipitated toxicities as a result of increased plasma levels of capecitabine.
In a white paper entitled Oral Oncology Treatment Regimens and the Role of Medication Therapy Management on Patient Adherence and Compliance, David Reese, Vice President Oncology at Tx Care Advantage discus how Medication Therapy Management (MTM) programs could intervene to improve medical adherence in both the oncology and non-oncology setting.
This review also documented the difficulties in accurately measuring patient adherence including:
- Inaccuracy of self-reporting
- Lack of applicability of external measurements such as pill counts
- Hawthorne effect: i.e. patient pill documentation reminds them to take next dose
The group suggests that using MTM programs, especially telephony systems involving oncology nurses and pharmacists and utilizing:
- Therapy support (dosing reminders)
- Education
- Side effect management
may be a cost-efficient methodology to improve medical adherence.
Although nurses are important intermediary educating patients about their oral chemotherapies, it does not appear that solely relying on nurses to monitor patient adherence will be sufficient, as indicated in a survey-based Japanese study.
As reported in May 12, 2014 | Oncology Nursing By Leah Lawrence
Systematic Nurse Involvement Key as Oral Chemotherapy Use Grows– at: http://www.cancernetwork.com/oncology-nursing/systematic-nurse-involvement-key-oral-chemotherapy-use-grows
Survey results indicated that 90% of nurses reported asking patients on oral chemotherapy about emergency contacts, side effects, and family/friend support. Nurses also provided patients with education materials on their assigned medication.
However, less than one-third of nurses asked if their patients felt confident about managing their oral chemotherapy.
“Nurses were less likely to ask adherence-related questions of patients with refilled prescriptions than of new patients,” the researchers wrote. “Regarding unused doses of anticancer agents, 35.5% of nurses reported that they did not confirm the number of unused doses when patients had refilled prescriptions.”
From the Roswell Park Cancer Institute blog post Making Mobile Health Work
https://www.roswellpark.org/partners-practice/white-papers/making-mobile-health-work
US physicians are recognizing the need for the adoption of mobile in their practice but choice of apps and mobile strategies must be carefully examined before implementation. In addition, most physicians are using mobile communications as a free-complementary service and these physicians are not being reimbursed for their time.
Some companies are providing their own oncology-related mobile app services:
CollabRx Announces Oncology-Specific Mobile App with Leading Site for Healthcare Professionals, MedPage Today
San Francisco, August 13, 2013 – CollabRx, Inc. (NASDAQ: CLRX), a healthcare information technology company focused on informing clinical decision making in molecular medicine, today announced a multi-year agreement with Everyday Health’s MedPage Today. The forthcoming app, which will target oncologists and pathologists, will focus on the molecular aspects of laboratory testing and therapy development. Over time, the expectation is that this app will serve as a comprehensive point of care resource for physicians and patients to obtain highly credible, expert-vetted and dynamically updated information to guide cancer treatment planning.
The McKesson Foundation’s Mobilizing for Health initiative
has awarded a grant to Partners HealthCare’s Center for Connected Health to develop a mobile health program that uses a smartphone application to help patients with cancer adhere to oral chemotherapy treatments and monitor their symptoms, FierceMobileHealthcare reports.
CancerNet announces mobile application (from cancer.net)
http://www.cancer.net/navigating-cancer-care/managing-your-care/mobile-applications
However, there is little evidence that the plethora of cancer-based apps is providing any benefit with regard to patient outcome or adherence, as reported in to an article in the Journal of Medical Internet Research, reported at FierceMobileHealthcare (Read more: Cancer smartphone apps for consumers lack effectiveness – FierceMobileHealthcare http://www.fiercemobilehealthcare.com/story/cancer-smartphone-apps-consumers-lack-effectiveness/2013-12-26#ixzz34ucdxVcU )
The report suggests that there are too many apps either offering information, suggesting behavior/lifestyle changes, or measuring compliance data but little evidence to suggest any of these are working the way they intended. The article suggests the plethora of apps may just be adding to the confusion.
Johnson&Johnson’s Wellness & Prevention unit has launched a health-tracking app Track Your Health. Although the company considers it a “gamification“ app, Track Your Health© operates to either feed data from other health tracking apps or allow the user to manually input data.
Read more: J&J launches ‘quantified self’ app to game patients into better behavior – FiercePharmaMarketing http://www.fiercepharmamarketing.com/story/jj-launches-quantified-self-app-game-patients-better-behavior/2014-05-28#ixzz34uhFDJr2
Even ASCO has a list of some oncology-related apps (http://connection.asco.org/commentary/article/id/3123/favorite-hematology-oncology-apps.aspx) and
NIH is offering grants for oncology-related app development (https://www.linkedin.com/groupItem?view=&gid=72923&type=member&item=5870221695683424259&qid=dbf53031-dd21-443c-9152-fad87f85d200&trk=groups_most_popular-0-b-ttl&goback=.gmp_72923)
As reports and clinicians have stated, we need health outcome data and clinical trials to determine the effective of these apps.
MyCyberDoctor™, a True Gamification App, Shows Great Results in Improving Diabetics Medical Adherence and Health Outcome
Most of the mobile health apps discussed above, would be classified as tracking apps, because the applications simply record a patient’s actions, whether filling a prescription, interacting with a doctor, nurse, pharmacist, or going to a website to gain information. However, as discussed before, there is no hard evidence this is really impacting health outcomes.
Another type of application, termed gamification apps, rely on role-playing by the patient to affect patient learning and ultimately behavior.
An interested twist on this method was designed by Akhila Satish, CEO and developer of CyberDoctor and a complementary application PatientPartner.
Ms. Akhila Satish, CEO CyberDoctor
Please watch video of interview with Akhila Satish, CEO of CyberDoctor at the Health 2.0 conference http://vimeo.com/51695558
And a video of the results of the PatientPartner clinical trial here: http://vimeo.com/79537738
As reported here, the PatientPartner application was used in the first IRB-approved mhealth clinical-trial to see if the gamification app could improve medical adherence and outcomes in diabetic patients. PatientPartner is a story-driven game in changing health behavior and biomarkers (blood glucose levels in this trial). In the clinical trial, 100 non-adherent patients with diabetes played the PatientPartner game for 15 minutes. Results were amazing, as the trial demonstrated an increase in patient adherence, with only 15 minutes of game playing.
Results from the study
Patients with diabetes who used PatientPartner showed significant improvement in three key areas – medication, diet, and exercise:
- Medication adherence increased by 37%, from 58% to 95% – equivalent to three additional days of medication adherence per week.
- Diet adherence increased by 24% – equivalent to two days of additional adherence a week.
- Exercise adherence increased by 14% – equivalent to one additional day of adherence per week.
- HbA1c (a blood sugar measure) decreased from 10.7% to 9.7%.
As mentioned in the article:
The unique, universal, non-disease specific approach allows PatientPartner to be effective in improving adherence in all patient populations.
PatientPartner is available in the iTunes store and works on the iPhone and iPod Touch. For information on PatientPartner, visit www.mypatientpartner.com.
Ms. Satish, who was named one of the top female CEO’s at the Health Conference, gratuitously offered to answer a few questions for Leaders in Pharmaceutical Business Intelligence (LPBI) on the feasibility of using such a game (role-playing) application to improve medical adherence in the oncology field.
LPBI: The results you had obtained with patient-compliance in the area of diabetes are compelling and the clinical trial well-designed. In the oncology field, due to the increase in use of oral chemotherapeutics, patient-compliance has become a huge issue. Other than diabetes, are there plans for MyCyberDoctor and PatientPartner to be used in other therapeutic areas to assist with patient-compliance and patient-physician relations?
Ms. Satish: Absolutely! We tested the application in diabetes because we wanted to measure adherence from an objective blood marker (hbA1c). However, the method behind PatientPartner- teaching patients how to make healthy choices- is universal and applicable across therapeutic areas.
LPBI: Recently, there have been a plethora of apps developed which claim to impact patient-compliance and provide information. Some of these apps have been niche (for example only providing prescription information but tied to pharmacy records and company databases). Your app seems to be the only one with robust clinical data behind it and approaches from a different angle, namely adjusting behavior using a gamefying experience and teaching the patient the importance of compliance. How do you feel this approach geared more toward patient education sets PatientPartner apart from other compliance-based apps?
Ms. Satish: PatientPartner really focuses on the how of patient decision making, rather than the specifics of each decision that is made. It’s a unique approach, and part of the reason PatientPartner works so effectively with such a short initial intervention! We are able to achieve more with less “app” time as a result of this method.
LPBI: There have been multiple studies attempting to correlate patient adherence, decision-making, and health outcome to socioeconomic status. In some circumstances there is a socioeconomic correlation while other cases such as patient-decision to undergo genetic testing or compliance to breast cancer treatment in rural areas, level of patient education may play a bigger role. Do you have data from your diabetes trial which would suggest any differences in patient adherence, outcome to any socioeconomic status? Do you feel use of PatientPartner would break any socioeconomic barriers to full patient adherence?
Ms. Satish: Within our trial, we had several different clinical sites. This helped us test the product out in a broad, socioeconomically diverse population. It is our hope that with a tool as easy to scale and use as PatientPartner we have the opportunity to see the product used widely, even in populations that are traditionally harder to reach.
LPBI: There has been a big push for the development of individual, personalized physician networks which use the internet as the primary point of contact between a primary physician and the patient. Individuals may sign up to these networks bypassing the traditional insurance-based networks. How would your application assist in these types of personalized networks?
Ms. Satish: PatientPartner can easily be plugged into any existing framework of communication between patient and provider. We facilitate patient awareness, engagement and accountability- all of which are important regardless of the network structure.
LBPI: Thank you Akhila!
A debate has begun about regulating mobile health applications, and although will be another post, I would just like to summarize a nice article in May, 2014 Oncology Times by Sarah Digiulo “Mobile Health Apps: Should They be Regulated?
In general, in the US there are HIPAA regulations about the dissemination of health related information between a patient and physician. Most of the concerns are related to personal health information made public in an open-access platform such as Twitter or Facebook.
In addition, according to Dr. Don Dizon M.D., Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, it may be more difficult to design applications directed against a vast, complex disease like cancer with its multiple subtypes than for diabetes.
Mobile Health Applications on Rise in Developing World: Worldwide Opportunity
According to International Telecommunication Union (ITU) statistics, world-wide mobile phone use has expanded tremendously in the past 5 years, reaching almost 6 billion subscriptions. By the end of this year it is estimated that over 95% of the world’s population will have access to mobile phones/devices, including smartphones.
This presents a tremendous and cost-effective opportunity in developing countries, and especially rural areas, for physicians to reach patients using mHealth platforms.
Drs. Clara Aranda-Jan Neo Mohutsiwa and Svetla Loukanova had conducted a systematic review of the literature on mHealth projects conducted in Africa[1] to assess the reliability of mobile phone and applications to assist in patient-physician relationships and health outcomes. The authors reviewed forty four studies on mHealth projects in Africa, determining their:
- strengths
- weaknesses
- opportunities
- threats
to patient outcomes using these mHealth projects. In general, the authors found that mHealth projects were beneficial for health-related outcomes and their success related to
- accessibility
- acceptance and low-cost
- adaptation to local culture
- government involvement
while threats to such projects could include
- lack of funding
- unreliable infrastructure
- unclear healthcare system responsibilities
Dr.Sreedhar Tirunagari, an oncologist in India, agrees that mHealth, especially gamification applications could greatly foster better patient education and adherencealthough he notes that mHealth applications are not really used in India and may not be of much use for those oncology patients living in rural areas, as cell phone use is not as prevalent as in the bigger inner cities such as Delhi and Calcutta.
Dr. Louis Bretes, an oncologist from Portugal, when asked
1) do you see a use for such apps which either track drug compliance or use gamification systems to teach patients the importance of continuing their full schedule of drug therapy
2) do you feel patient- drug compliance issues in the oncology practice is due to lack of information available to the patient or issues related to drug side effects?
“I think that Apps could help in this setting, we are in
Informatics era but..
The main question is that chronic patients are special ones.
Cancer patients have to deal with prognosis, even in therapies
with curative intent such as aromatase inhibitors are potent
Drugs that can cure; only in the future the patients know.
But meanwhile he or she has to deal with side-effects every day. A PC can help but suffer this symptoms…it. Is a real problem believe me!”
“The main app is his/her doctor”
I would like to invite all oncologists to answer the poll question ABOVE about the use of such gamification apps, like PatientPartner, for improving medical adherence to oral chemotherapy.
UPDATE 5/15/2019
The results of the above poll, although limited, revealed some interesting insights. Although only five oncologists answered the poll whether they felt gamification applications could help with oral chemotherapy patient adherence, all agreed it would be worthwhile to develop apps based on gamification to assist in the outpatient setting. In addition, one oncologist felt that the success of mobile patient adherence application would depend on the type of cancer. None of the oncologist who answered the survey thought that gamification apps would have no positive effect on patient adherence to their chemotherapy. With this in light, a recent paper by Joel Fishbein of University of Colorado and Joseph Greer from Massachusetts General Hospital, describes the development of a mobile application, in clinical trial, to promote patient adherence to their oral chemotherapy.
Mobile Applications to Promote Adherence to Oral Chemotherapy and Symptom Management: A Protocol for Design and Development
Mobile Application to Promote Adherence to Oral Chemotherapy and Symptom Management: A Protocol for Design and Development. Fishbein JN, Nisotel LE, MacDonald JJ, Amoyal Pensak N, Jacobs JM, Flanagan C, Jethwani K Greer JA. JMIR Res Protoc. 2017 Apr 20;6(4):e62. doi: 10.2196/resprot.6198.
Abstract
BACKGROUND:
Oral chemotherapy is increasingly used in place of traditional intravenous chemotherapy to treat patients with cancer. While oral chemotherapy includes benefits such as ease of administration, convenience, and minimization of invasive infusions, patients receive less oversight, support, and symptom monitoring from clinicians. Additionally, adherence is a well-documented challenge for patients with cancer prescribed oral chemotherapy regimens. With the ever-growing presence of smartphones and potential for efficacious behavioral intervention technology, we created a mobile health intervention for medication and symptom management.
OBJECTIVE:
The objective of this study was to develop and evaluate the usability and acceptability of a smartphone app to support adherence to oral chemotherapy and symptom management in patients with cancer.
METHODS:
We used a 5-step development model to create a comprehensive mobile app with theoretically informed content. The research and technical development team worked together to develop and iteratively test the app. In addition to the research team, key stakeholders including patients and family members, oncology clinicians, health care representatives, and practice administrators contributed to the content refinement of the intervention. Patient and family members also participated in alpha and beta testing of the final prototype to assess usability and acceptability before we began the randomized controlled trial.
RESULTS:
We incorporated app components based on the stakeholder feedback we received in focus groups and alpha and beta testing. App components included medication reminders, self-reporting of medication adherence and symptoms, an education library including nutritional information, Fitbit integration, social networking resources, and individually tailored symptom management feedback. We are conducting a randomized controlled trial to determine the effectiveness of the app in improving adherence to oral chemotherapy, quality of life, and burden of symptoms and side effects. At every stage in this trial, we are engaging stakeholders to solicit feedback on our progress and next steps.
CONCLUSIONS:
To our knowledge, we are the first to describe the development of an app designed for people taking oral chemotherapy. The app addresses many concerns with oral chemotherapy, such as medication adherence and symptom management. Soliciting feedback from stakeholders with broad perspectives and expertise ensured that the app was acceptable and potentially beneficial for patients, caregivers, and clinicians. In our development process, we instantiated 7 of the 8 best practices proposed in a recent review of mobile health app development. Our process demonstrated the importance of effective communication between research groups and technical teams, as well as meticulous planning of technical specifications before development begins. Future efforts should consider incorporating other proven strategies in software, such as gamification, to bolster the impact of mobile health apps. Forthcoming results from our randomized controlled trial will provide key data on the effectiveness of this app in improving medication adherence and symptom management.
TRIAL REGISTRATION:
ClinicalTrials.gov NCT02157519; https://clinicaltrials.gov/ct2/show/NCT02157519 (Archived by WebCite at http://www.webcitation.org/6prj3xfKA).
In this paper, Fishbein et al. describe the methodology of the developoment of a mobile application to promote oral chemotherapy adherence. This mobile app intervention was named CORA or ChemOtheRapy Assistant.
Of the approximately 325,000 health related apps on the market (as of 2017), the US Food and Drug Administration (FDA) have only reviewed approximately 20 per year and as of 2016 cleared only about 36 health related apps.
According to industry estimates, 500 million smartphone users worldwide will be using a health care application by 2015, and by 2018, 50 percent of the more than 3.4 billion smartphone and tablet users will have downloaded mobile health applications. However, there is not much scientific literature providing a framework for design and creation of quality health related mobile applications.
Methods
The investigators separated the app development into two phases: Phase 1 consisted of the mobile application development process and initial results of alpha and beta testing to determine acceptability among the major stakeholders including patients, caregivers, oncologists, nurses, pharmacists, pharmacologists, health payers, and patient advocates. Phase 1 methodology and results were the main focus of this paper. Phase 2 consists of an ongoing clinical trial to determine efficacy and reliability of the application in a larger number of patients at different treatment sites and among differing tumor types.
The 5 step development process in phase 1 consisted of identifying features, content, and functionality of a mobile app in an iterative process, including expert collaboration and theoretical framework to guide initial development.
There were two distinct teams: a research team and a technical team. The multidisciplinary research team consisted of the principal investigator, co-investigators (experts in oncology, psychology and psychiatry), a project director, and 3 research assistants.
The technical team consisted of programmers and project managers at Partners HealthCare Connected Health. Stakeholders served as expert consultants including oncologists, health care representatives, practice administrators, patients, and family members (care givers). All were given questionaires (HIPAA compliant) and all involved in alpha and beta testing of the product.
There were 5 steps in the development process
- Implementing a theoretical framework: Patients and their family caregivers now bear the primary responsibility for their medical adherence especially to oral chemotherapy which is now more frequently administered in the home setting not in the clinical setting. Four factors were identified as the most important barriers to oral chemotherapy adherence: complexity of medication regimes, symptom burden, poor self-management of side effects, and low clinical support. These four factors were integral in the design of the mobile app and made up a conceptual framework in its design.
- Conducting Initial Focus Group Interviews with key stakeholders: Stakeholders were taken from within and outside the local community. In all 32 stakeholders served as study collaborators including 8 patient/families, 8 oncologists/clinicians, 8 cancer practice administrators, and 8 representatives of the health system, community, and overall society. The goal of these focus groups were to obtain feedback on the proposed study and design included perceived importance of monitoring of adherence to oral chemotherapy, barriers to communication between patients and oncology teams regarding side effects and medication adherence, potential role of mobile apps to address barriers of quality of cancer care, potential feasibility, acceptability, and usage and feedback on the overall study design.
- Creation of Wireframes (like storyboards or page designs) and Collecting Initial Feedback: The research and design team, in conjunction with stakeholder input, created content wireframes, or screen blueprints) to provide a visual guide as to what the app would look like. These wireframes also served as basis for what the patient interviews would look like on the application. A total of 10 MGH (Massachusetts General Hospital) patients (6 female, 4 male) and most with higher education (BS or higher) participated in the interviews and design of wireframes. Eight MGH clinicians participated in this phase of wireframe design.
- Developing, Programming, and Refining the App: CORA was designed to be supported by PHP/MySQL databases and run on LAMP hosts (Linux, Apache, MySQL, Perl/PHP/Python) and fully HIPAA compliant. Alpha testing was conducted with various stakeholders and the app refined by the development team (technical team) after feedback.
- Final beta testing and App prototype for clinical trial: The research team considered the first 5 participants enrolled in the subsequent clinical trial for finalization of the app prototype.
There were 7 updated versions of the app during the initial clinical trial phase and 4 updates addressed technical issues related to smartphone operating system upgrades.
Finally, the investigators list a few limitations in their design and study of this application. First the patient population was homogenous as all were from an academic hospital setting. Second most of the patients were of Caucasian ethnic background and most were highly educated, all of which may introduce study bias. In addition, CORA was available on smartphone and tablet only, so a larger patient population who either have no access to these devices or are not technically savvy may experience issues related to this limitation.
In addition other articles on this site related to Mobile Health applications and Health Outcomes include
Medical Applications and FDA regulation of Sensor-enabled Mobile Devices: Apple and the Digital Health Devices Market
How Social Media, Mobile Are Playing a Bigger Part in Healthcare
E-Medical Records Get A Mobile, Open-Sourced Overhaul By White House Health Design Challenge Winners
Qualcomm Ventures Qprize Regional Competition: MediSafe, an Israeli start-up in the personal health field, is the 2014 Winner of a $100,000 Prize
Friday, April 4 8:30 am- 9:30 am Science Track: Mobile Technology and 3D Printing: Technologies Gaining Traction in Biotech and Pharma – MassBio Annual Meeting 2014, Royal Sonesta Hotel, Cambridge, MA
Information Security and Privacy in Healthcare is part of the 2nd Annual Medical Informatics World, April 28-29, 2014, World Trade Center, Boston, MA
Post Acute Care – Driver of Variation in Healthcare Costs
Kaiser data network aims to improve cancer, heart disease outcomes
Additional references
- Aranda-Jan CB, Mohutsiwa-Dibe N, Loukanova S: Systematic review on what works, what does not work and why of implementation of mobile health (mHealth) projects in Africa. BMC public health 2014, 14:188.
Prof. Illana Gozes discovered Novel Protein Fragments that have proven Protective Properties for Cognitive Functioning
Posted in Alzheimer's Disease, Etiology on June 3, 2014| Leave a Comment »
Prof. Illana Gozes discovered Novel Protein Fragments that have proven Protective Properties for Cognitive Functioning
Reporter: Aviva Lev-Ari PhD, RN
Novel Protein Fragments May Protect Against Alzheimer’s – DIscovery @ Tel Aviv School of Medicine
Tue, 13 May 2014
TAU RESEARCHER’S DISCOVERY CAN LEAD TO NEW DRUG CANDIDATES TO TREAT THE NEURODEGENERATIVE DISEASE
The devastating loss of memory and consciousness in Alzheimer’s disease is caused by plaque accumulations and tangles in neurons, which kill brain cells. Alzheimer’s research has centered on trying to understand the pathology as well as the potential protective or regenerative properties of brain cells as an avenue for treating the widespread disease.
Now Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University‘s Sagol School of Neuroscience, has discovered novel protein fragments that have proven protective properties for cognitive functioning.
In a study published in the Journal of Alzheimer’s Disease, Prof. Gozes examined the protective effects of two newly discovered protein fragments in mice afflicted with Alzheimer’s disease-like symptoms. Her findings have the potential to serve as a pipeline for new drug candidates to treat the disease.
NAP time for Alzheimer’s
“Several years ago we discovered that NAP, a snippet of a p
rotein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer’s,” said Prof. Gozes. “Now, we’re investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery.”
Prof. Gozes’ research focused on the microtubule network, a crucial part of cells in our bodies. Microtubules act as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s, this network breaks down, hindering motor abilities and cognitive function.
“NAP operates through the stabilization of microtubules — tubes within the cell which maintain cellular shape. They serve as ‘train tracks’ for movement of biological material,” said Prof. Gozes. “This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer’s disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell.”
Down the tubes
In her new study, Prof. Gozes and her team looked at the subunit of the microtubule — the tubulin — and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer’s; increased tangle accumulation is indicative of cognitive deterioration. Prof. Gozes decided to test both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, she tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients’ brains.
“From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline,” said Prof. Gozes. “We tested one compound — a tubulin fragment — and saw that it protected against cognitive deficits. When we looked at the ‘dementia’-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels.”
Prof. Gozes and her team also measured the brain-to-body mass ratio, an indicator of brain degeneration, and saw a significant decrease in the mouse model compared to normal mice. Following the introduction of the tubulin fragments, however, the mouse’s brain to body ratio returned to normal. “We clearly see here the protective effect of the treatment,” said Prof. Gozes. “We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models.”
SOURCE
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