Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘Axon’


Remyelination of axon requires Gli1 inhibition

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Inhibition of Gli1 Enhances Remyelination Abilities of Endogenous Stem Cell Populations

 

nodes_of_ranvier

https://beyondthedish.files.wordpress.com/2015/12/nodes_of_ranvier.jpg

 

If myelin is damaged, the speed of nerve impulse transmission slows substantially. Multiple sclerosis is one example of a disease that causes systematic loss of the myelin sheath. Inflammatory demyelinating diseases also cause progressive damage and loss of the myelin sheath. Regenerating the myelin sheath in these patients is one of the goals of regenerative medicine.

A good deal of data tells us that endogenous remyelination does occur. Unfortunately, this process is overwhelmed by the degree of demyelination in these diseases. A stem cell population called the parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells in the brain are known to remyelinate demyelinated axons.

The Salzer laboratory at the New York Neuroscience Institute examined the ability of a specific adult neural stem cell population to remyelinate axons. These stem cells expressed the transcription factor Gli1.

Salzer and his team showed that this subventricular zone-specific group of neural stem cells were efficiently recruited to demyelinated portions of the brain. This same neural stem cell population was never observed entering healthy axon tracts. This finding shows that these cells seem to specialize in making new myelin sheaths for damaged axon tracts.

Since these neural stem cells expressed Gli1, and since there are drugs that can inhibit Gli1 activity, Salzer’s group wanted to show that Gli1 was a necessary factor for neural stem cell activity. Surprisingly, differentiation of these neural stem cells into oligodendrocytes (which make myelin and remyelinate axons) is significantly enhanced by inhibition of Gli1.

A specific signaling pathway called the hedgehog pathway is known to activate Gli1 and other members of the Gli gene family. However, when the hedgehog pathway in these neural stem cells was completely inhibited, it did not have the same effect and Gli1 inhibition. This suggests that Gli1 is doing more than responding to the hedgehog pathway in these neural stem cells.

Salzer and his colleagues showed that Gli1 inhibition improved myelin deposition in an animal model of experimental autoimmune encephalomyelitis; an inflammatory demyelination disease. Thus, inhibition of Gli1 activity in this preclinical model system increase regeneration of the myelin sheath in demyelinated neurons.

This work elegantly showed that endogenous neural stem cells that can remyelinate axons are present and can be activated by inhibiting Gli1. Furthermore, this activation will nicely enhance the therapeutic capacity of these endogenous cells. This potentially identifies a new therapeutic avenue for the treatment of demyelinating disorders.

This work was published in Nature. 2015 Oct 15;526(7573):448-52. doi: 10.1038/nature14957.

 

Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination
Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination.

 Nature. 2015 Oct 15;526(7573):448-52.   http://dx.doi.org:/10.1038/nature14957   Epub 2015 Sep 30.

Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.

 

Advertisements

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

 

Scripps Research Institute Scientists Discover Key Signaling Pathway that Makes Young Neurons Connect

LA JOLLA, CA – June 20, 2013 – Neuroscientists at The Scripps Research Institute (TSRI) have filled in a significant gap in the scientific understanding of how neurons mature, pointing to a better understanding of some developmental brain disorders.

In the new study, the researchers identified a molecular program that controls an essential step in the fast-growing brains of young mammals. The researchers found that this signaling pathway spurs the growth of neuronal output connections by a mechanism called “mitochondrial capture,” which has never been described before.

“Mutations that may affect this signaling pathway already have been found in some autism cases,” said TSRI Professor Franck Polleux, who led the research, published June 20, 2013 in the journal Cell.

Branching Out

Polleux’s laboratory is focused on identifying the signaling pathways that drive neural development, with special attention to the neocortex—a recently evolved structure that handles the “higher” cognitive functions in the mammalian brain and is highly developed in humans.

In a widely cited study published in 2007, Polleux’s team identified a trigger of an early step in the development of the most important class of neocortical neurons. As these neurons develop following asymmetric division of neural stem cells, they migrate to their proper place in the developing brain. Meanwhile they start to sprout a root-like mesh of input branches called dendrites from one end, and, from the other end, a long output stalk called an axon. Polleux and his colleagues found that the kinase LKB1 provides a key signal for the initiation of axon growth in these immature cortical neurons.

In the new study, Polleux’s team followed up this discovery and found that LKB1 also is crucially important for a later stage of these neurons’ development: the branching of the end of the axon onto the dendrites of other neurons.

“In experiments with mice, we knocked the LKB1 gene out of immature cortical neurons that had already begun growing an axon, and the most striking effect was a drastic reduction in terminal branching,” said Julien Courchet, a research associate in the Polleux laboratory who was a lead co-author of the study. “We saw this also in lab dish experiments, and when we overexpressed the LKB1 gene, the result was a dramatic increase in axon branching.”

Further experiments by Courchet showed that LKB1 drives axonal branching by activating another kinase, NUAK1. The next step was to try to understand how this newly identified LKB1-NUAK1 signaling pathway induced the growth of new axon branches.

Stopping the Train in Its Tracks

Following a thin trail of clues, the researchers decided to look at the dynamics of microtubules. These tiny railway-like tracks are laid down within axons for the efficient transport of molecular cargoes and are altered and extended during axonal branching. Although they could find no major change in microtubule dynamics within immature axons lacking LKB1 or NUAK1, the team did discover one striking abnormality in the transport of cargoes along these microtubules. Tiny oxygen-reactors called mitochondria, which are the principal sources of chemical energy in cells, were transported along axons much more actively—and by contrast, became almost immobile when LKB1 and NUAK1 were overexpressed.

But the LKB1-NUAK1 signals weren’t just immobilizing mitochondria randomly. They were effectively inducing their capture at points on the axons where axons form synaptic connections with other neurons. “When we removed LKB1 or NUAK1 in cortical neurons, the mitochondria were no longer captured at these points,” said Tommy Lewis, Jr., a research associate in the Polleux Laboratory who was co-lead author of the study.

“We argue that there must be an active ‘homing factor’ that specifies where these mitochondria stop moving,” said Polleux. “And we think that this is essentially what the LKB1-NAUK1 signaling pathway does here.”

Looking Ahead

Precisely how the capture of mitochondria at nascent synapses promotes axonal branching is the object of a further line of investigation in the Polleux laboratory. “We think that we have uncovered something very interesting about mitochondrial function at synapses,” Polleux said.

In addition to its basic scientific importance, the work is likely to be highly relevant medically. Developmentally related brain disorders such as epilepsy, autism and schizophrenia typically involve abnormalities in neuronal connectivity. Recent genetic surveys have found NUAK1-related gene mutations in some children with autism, for example. “Our study is the first one to identify that NUAK1 plays a crucial role during the establishment of cortical connectivity and therefore suggests why this gene might play a role in autistic disorder,” Polleux says.

He notes, too, that declines in normal mitochondrial transport within axons have been observed in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. “In the light of our findings, we wonder if the decreased mitochondrial mobility observed in these cases might be due not to a transport defect, but instead to a defect in mitochondrial capture in aging neurons,” he said. “We’re eager to start doing experiments to test such possibilities.”

Other contributors to the study, “Terminal Axon Branching Is Regulated by the LKB1-NUAK1 Kinase Pathway via Presynaptic Mitochondrial Capture,” were Sohyon Lee, Virginie Courchet and Deng-Yuan Liou of TSRI, and Shinichi Aizawa of the RIKEN Institute of Kobe, Japan.

The study was funded in part by the National Institutes of Health (grants R01AG031524 and 5F32NS080464), ADI-Novartis, Fondation pour la Recherche Medicale, and the Philippe Foundation.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

# # #

For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8136
press@scripps.edu

http://www.scripps.edu/news/press/2013/20130620polleux.html?elq=a37dd39263d54de38cea68188c307bf6&elqCampaignId=17

Read Full Post »