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March 21, 2006 -- No. 158
Study shows how neurons become damaged
in myelin-related diseases such as multiple sclerosis
CHAPEL HILL – Multiple sclerosis leads to degeneration of axons, the long fibers that carry electrical impulses from nerve cell to nerve cell. How that damage occurs has previously been unclear – but, for the first time, researchers at the University of North Carolina at Chapel Hill have found that disrupting a region that connects the axon to its protective coating causes axons to deteriorate.
"Much like a live electrical wire, axons require insulation in order for impulses to travel without leakage or loss of strength," said Dr. Manzoor Bhat, lead author of the study and associate professor in the UNC School of Medicine’s department of cell and molecular physiology.
That insulator is myelin, and it is sealed onto the axon by regions known as axo-glial junctions.
Bhat and colleagues found that in mice missing either one of two proteins required for the formation of axo-glial junctions, axons of particular nerve cells degenerated.
The study also showed that axo-glial junctions are critical to the axon’s "scaffolding," or cytoskeleton at the unique paranodal region.
"Identification of a molecular link between axo-glial junctions and axonal degeneration opens a new avenue of exploration in myelin-related diseases," said Bhat, also a member of the UNC Neuroscience Center and the Neurodevelopmental Disorders Research Center.
Understanding why axons degenerate when there is defective insulation may provide clues about axonal death in myelin-related diseases such as multiple sclerosis, or MS.
The study is published in the March 20 issue of the Proceedings of the National Academy of Sciences.
In 2001, Bhat created a "knockout mouse" genetically engineered to possess a mutation in a protein, NCP1/Caspr1, which creates the axo-glial junctions. In the current study, the researchers used these mice as well as knockout mice missing another important protein, CGT, which is crucial to axo-glial junction formation. Dr. Brian Popko, now of the University of Chicago, created the CGT mutant mice when he was a faculty member at UNC.
Both of these knockout mice have lost motor control, stumbling and falling when trying to walk. In the current study, the researchers found one likely reason why: Both the mice showed deterioration of axons of particular nerve cells (Purkinje neurons) in the cerebellum.
The researchers also used a method called immunoprecipitation to identify proteins that interact with NCP1. "Every protein in our body has its own interacting partners," Bhat said. They found that NCP1 works as part of a complex with proteins found in the cytoskeleton of axons.
"That tells us that axo-glial junctions are linked to the cytoskeleton of the axon. That means that those junctions are not just sitting at the surface, but they are linked with the core of the axon," Bhat said. "So the link that NCP1 makes between the axonal cytoskeleton and these junctions is critical to stabilize this region."
"This story illustrates the power of basic research in helping solve medical mysteries, such as what goes wrong in the cells of people with multiple sclerosis, a chronic, often debilitating disease that usually strikes in the prime of life," said Dr. Laurie Tompkins, a program director at the National Institute of General Medical Sciences, which partially funded the research.
Bhat and colleagues are now working to identify other proteins that act in complex with NCP1 and other axo-glial junction proteins.
"If we can understand how this whole region is orchestrated, then we might be able to design strategies to stop it from disintegrating in a disease such as multiple sclerosis," Bhat said.Other UNC authors of the study are doctoral candidate German P. Garcia-Fresco of the Curriculum in Neurobiology; Dr. Aurea D. Sousa, research associate in the department of cell and molecular physiology; Anilkumar M. Pillai, research assistant in the department of cell and molecular physiology; Dr. Sheryl S. Moy, research associate professor in the department of psychology; and Dr. Jacqueline N. Crawley, professor in the department of psychology.
Other authors are Dr. Jeff Dupree, assistant professor at Virginia Commonwealth University; and Dr. Lino Tessarollo, a principal investigator with the National Cancer Institute.
Funding was provided by the National Institute of General Medical Sciences and the National Cancer Institute, both components of the National Institutes of Health; and the State of North Carolina.
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