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Dysregulation of ncRNAs in association with Neurodegenerative Disorders
Curator: Amandeep Kaur
Research over the years has added evidences to the hypothesis of “RNA world” which explains the evolution of DNA and protein from a simple RNA molecule. Our understanding of RNA biology has dramatically changed over the last 50 years and rendered the scientists with the conclusion that apart from coding for protein synthesis, RNA also plays an important role in regulation of gene expression.
The universe of non-coding RNAs (ncRNAs) is transcending the margins of preconception and altered the traditional thought that the coding RNAs or messenger RNAs (mRNAs) are more prevalent in our cells. Research on the potential use of ncRNAs in therapeutic relevance increased greatly after the discovery of RNA interference (RNAi) and provided important insights into our further understanding of etiology of complex disorders.
Latest research on neurodegenerative disorders has shown the perturbed expression of ncRNAs which provides the functional association between neurodegeneration and ncRNAs dysfunction. Due to the diversity of functions and abundance of ncRNAs, they are classified into Housekeeping RNAs and Regulatory ncRNAs.
The best known classes of ncRNAs are the microRNAs (miRNAs) which are extensively studied and are of research focus. miRNAs are present in both intronic and exonic regions of matured RNA (mRNA) and are crucial for development of CNS. The reduction of Dicer-1, a miRNA biogenesis-related protein affects neural development and the elimination of Dicer in specifically dopaminergic neurons causes progressive degeneration of these neuronal cells in striatum of mice.
A new class of regulatory ncRNAs, tRNAs-derived fragments (tRFs) is superabundantly present in brain cells. tRFs are considered as risk factors in conditions of neural degeneration because of accumulation with aging. tRFs have heterogenous functions with regulation of gene expression at multiple layers including regulation of mRNA processing and translation, inducing the activity of silencing of target genes, controlling cell growth and differentiation processes.
The existence of long non-coding RNAs (lncRNAs) was comfirmed by the ENCODE project. Numerous studies reported that approximately 40% of lncRNAs are involved in gene expression, imprinting and pluripotency regulation in the CNS. lncRNA H19 is of paramount significance in neural viability and contribute in epilepsy condition by activating glial cells. Other lncRNAs are highly bountiful in neurons including Evf2 and MALAT1 which play important function in regulating neural differentiation and synapse formation and development of dendritic cells respectively.
Recently, a review article in Nature mentioned about the complex mechanisms of ncRNAs contributing to neurodegenerative conditions. The ncRNA-mediated mechanisms of regulation are as follows:
Epigenetic regulation: Various lncRNAs such as BDNF-AS, TUG1, MEG3, NEAT1 and TUNA are differentially expressed in brain tissue and act as epigenetic regulators.
RNAi: RNA interference includes post-transcriptional repression by small-interfering RNAs (siRNAs) and binding of miRNAs to target genes. In a wide spectrum of neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease, Amyotrophic lateral sclerosis, Fragile X syndrome, Frontotemporal dementia, and Spinocerebellar ataxia, have shown perturbed expression of miRNA.
Alternative splicing: Variation in splicing of transcripts of ncRNAs has shown adverse affects in neuropathology of degenerative diseases.
mRNA stability: The stability of mRNA may be affected by RNA-RNA duplex formation which leads to the degradation of sense mRNA or blocking the access to proteins involved in RNA turnover and modify the progression of neurodegenerative disorders.
Translational regulation: Numerous ncRNAs including BC200 directly control the translational process of transcripts of mRNAs and effect human brain of Alzheimer’s disease.
Molecular decoys: Non-coding RNAs (ncRNAs) dilute the expression of other RNAs by molecular trapping, also known as competing endogenous RNAs (ceRNAs) which hinder the normal functioning of RNAs. The ceRNAs proportion must be equivalent to the number of target miRNAs that can be sequestered by each ncRNAs in order to induce consequential de-repression of the target molecules.
The unknown functions of numerous annotated ncRNAs may explain the underlying complexity in neurodegenerative disorders. The profiling of ncRNAs of patients suffering from neurodevelopmental and neurodegenerative conditions are required to outline the changes in ncRNAs and their role in specific regions of brain and cells. Analysis of Large-scale gene expression and functional studies of ncRNAs may contribute to our understanding of these diseases and their remarkable connections. Therefore, targeting ncRNAs may provide effective therapeutic perspective for the treatment of neurodegenerative diseases.
Precision Medicine has helped transform cancer care from one-size-fits-all chemotherapy to a new era, where patients’ tumors can be analyzed and therapy selected based on their genetic makeup. Until now, however, precision medicine’s impact has been far less in other therapeutic areas, many of which are ripe for transformation. Efforts are underway to bring the successes of precision medicine to neurology, immunology, ophthalmology, and other areas. This move raises key questions of how the lessons learned in oncology can be used to advance precision medicine in other fields, what types of data and tools will be important to personalizing treatment in these areas, and what sorts of partnerships and payer initiatives will be needed to support these approaches and their ultimate commercialization and use. The panel will also provide an in depth look at precision medicine approaches aimed at better understanding and improving patient care in highly complex disease areas like neurology.
Speaker panel: The big issue now with precision medicine is there is so much data and hard to put experimental design and controls around randomly collected data.
The frontier is how to CURATE randomly collected data to make some sense of it
One speaker was at a cancer meeting and the oncologist had no idea what to make of genomic reports they were given. Then there is a lack of action or worse a misdiagnosis.
So for e.g. with Artificial Intelligence algorithms to analyze image data you can see things you can’t see with naked eye but if data quality not good the algorithms are useless – if data not curated properly data is wasted
Data needs to be organized and curated.
If relying of AI for big data analysis the big question still is: what are the rates of false negative and false positives? Have to make sure so no misdiagnosis.
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Can new imaging techniques help determine who will develop Alzheimer’s before symptoms show? Sperling says early detection and prevention research is the best defense against a disease we discover too late to treat.
A new proof-of-concept study shows that plasma concentrations of precursor fragments of the neuropeptide enkephalin (proenkephalin A, or PENK-A) are elevated in patients with acute stroke compared with those with TIA and nonischemic events.
Researchers are making efforts to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease.
Although the mature neuropeptides are degraded within minutes, their precursor fragments are much more stable and represent neuropeptide synthesis in stoichiometric relations. “They are therefore well suited as biomarkers and may be suitable for measurement in clinical settings,” said Dr. Doehner.
The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders.
{Ernst A., Kohrle J., Bergmann A.; Proenkephalin A 119—159, a stable proenkephalin. A precursor fragment identified in human circulation, Peptides 27 2006 1835-1840
Ernst A., Suhr J., Kohrle J., Bergmann A.; Detection of stable N-terminal protachykinin A immunoreactivity in human plasma and cerebrospinal fluid, Peptides 29 2008 1201-1206}
Researchers are making efforts to use these precursor fragments as markers to distinguish an ischemic stroke from a transient ischemic attack (TIA) or an intracerebral hemorrhage.
The authors strongly hope that it may help to advance the use of biomarkers in the clinical evaluation of stroke patients.
Despite the limitations, elevated PENK-A levels correlated with stroke severity and with brain lesion size, and they predicted mortality and more functional disability.
“There is clearly an unmet need to establish biomarker-guided prognostic and functional evaluations for patients with stroke, said the lead author Wolfram Doehner, MD, PhD, from the Center for Stroke Research, in Berlin, Germany
The new report was published in Journal of the American College of Cardiology.
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