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Charcot-Marie-Tooth (CMT) disorder may not be as familiar to most people as amyotrophic lateral sclerosis (ALS) or Parkinson's disease, but all are neurodegenerative diseases that eventually cause dysfunction and kill particular neurons in either the brain or the peripheral nervous system.

Now new research on two new mutations associated with CMT may lead to a better understanding of how cells die in CMT and other neurodegenerative diseases, according to Dr. Ronald Liem, professor of pathology and anatomy/cell biology; Dr. Raul Perez-Olle, his Ph.D. student; and Dr. Conrad Leung, assistant professor of clinical pathology.

The researchers found that both mutations caused abnormal aggregates or bundles of neuronal proteins called neurofilaments, similar to the protein agglomerations found in the nervous tissue of other neurodegenerative diseases, such as ALS and Parkinson's. The research was published in the December issue of the Journal of Cell Science.

These abnormal aggregates of filaments may lead to the degeneration of peripheral nerves that is characteristic of CMT. If so, understanding CMT could provide insights into cell death in other neurodegenerative diseases that are also characterized by aggregates of neuronal proteins.

In Charcot-Marie-Tooth disorder, patients slowly lose their ability to use their hands, feet, lower legs, and arms as the peripheral nerves to the extremities degenerate. Muscles in the extremities then become weak through the lack of use. The disease also affects the sensory nerves. The inherited disease affects about one person in every 2,500 and some become extremely disabled. The only treatment is physical therapy to maintain muscle strength.

The disorder is associated with mutations in approximately 14 different genes, but traditionally the disease has been divided into two classes. One class affects Schwann cells, which wrap axons by forming a myelin sheath, and causes a loss of myelin around long neuronal axons of motor and sensory neurons that extend into the arms and legs. The other class causes defects in the axons of the peripheral neurons themselves.

In their study, the researchers looked at how two mutations linked to the axonal form of CMT disrupt the function of the proteins for which they code. The two mutations, (which were recently identified by a research team led by Dr. Oleg Evgrafov, a research scientist from the Research Center for Medical Genetics in Moscow now in the Columbia Genome Center), occur in the same protein, NF-L, a subunit of neurofilaments. Neurofilaments form from several types of subunits and branch out throughout a neuron's axons to provide mesh-like structural support. A defect in neurofilaments could disrupt other important functions inside the cell and lead to the disease.

When the mutant genes were expressed in cells that lacked their own ability to make the NF-L subunit, neither mutant protein could form normal-looking structures. One mutant protein could not form filaments under any conditions and the altered proteins stuck together in aggregates. The second mutant protein also amassed together and did not form filaments unless other types of normal filament subunits were present. When other subunits were present, these second mutated proteins formed filaments that made abnormal bundles instead of normal filamentous networks.

The researchers say the results suggest the two mutations lead to neurodegeneration in the disorder, but it is unclear how the process happens. It's possible the neurofilament bundles somehow disrupt the transport of proteins and organelles along microtubules, another set of structural proteins that run from the cell's nucleus to the end of a neuron's axon.

Other research supports the disrupted transport theory. A mutation in a protein that moves organelles down microtubules, called kinesin, also causes CMT. A group of CMT researchers in England recently found that the neurofilament mutations studied by Drs. Liem, Perez-Olle, and Leung block the transport of mitochondria through the axon. The English researchers propose that the lack of mitochondria starves the axon terminals of energy that could lead to cell degeneration and death.

Mutations in other neurofilament subunits are associated with other neurodegenerative diseases, like ALS and Parkinson's, but it is unknown how the mutations affect disease progression.

Drs. Liem and Perez-Olle are now conducting experiments on the effects of the two NF-L mutations in neurons. They are also planning to examine patients for the presence of neurofilament mutations and signs of neurofilament aggregations and expect to construct a mouse model to see how the aggregations affect the disease.

Dr. Robert Lovelace, professor of neurology and chairman of the medical advisory board of the Charcot-Marie-Tooth Association, says, "Looking further down the pathway from neurofilament genes may lead us to a way of treating CMT. Extending this concept also could possibly help us understand other diseases which manifest neurofilament aggregates."

The research was supported by the National Institutes of Health. Dr. Perez-Olle is supported by a fellowship from the Charcot-Marie-Tooth Association and was recently named the association's Carolyn Redell Fellow, which honors the founder of the New York-based CMT support group.


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