Studies Of Hereditary Neurological Disease

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The purpose of the Neurogenetics Branch is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. Particular areas of research interest include the polyglutamine expansion diseases (Huntington's disease, Kennedy's disease, and spinocerebellar ataxia), spinal muscular atrophy, Charcot-Marie-Tooth disease, muscular dystrophy, hereditary motor neuron disease, and Friedreich's ataxia. The disease mechanisms are studied in cell culture and other model systems. A related area of investigation is the mechanism of androgen effects on muscle strength and motor neuron survival. A genetic outreach program is intended to identify and characterize patients and families with hereditary neurological diseases. A trial of gentamicin treatment in patients with Duchenne muscular dystrophy has been completed, and further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We have implicated a critical nuclear factor (CBP) and cellular process (protein acetylation) in the pathogenesis of polyglutamine expansion neurodegenerative disease, and we have identified treatments (histone deacetylase inhibition and RNA inhibition) that mitigate polyglutamine toxicity. (2) We have further characterized the pathway of neuronal death in a cell culture model of polyglutamine disease. (3) We have identified specific factors stimulated by androgens in cultured neuronal cells, which are candidates for promoting motor neuron survival. (4) We have helped to narrow the search for the genetic defects responsible for autosomal dominant forms of axonal neuropathy and motor neuronopathy that are mapped to chromosomes 7 and 9 respectively, and we have gathered families with hereditary neuropathy and vocal fold paralysis (Charcot-Marie-Tooth disease type 2C) for genetic linkage analysis. (5) We have developed a trial of anti-oxidant (idebenone) therapy for patients with Friedreich's ataxia. (6) We have carried out a trial of gentamicin treatment in patients with Duchenne muscular dystrophy, and characterized a behavioral deficit in mdx, a mouse model for this disease. (7) We have created a mouse model of spinal and bulbar muscular atrophy (Kennedy's disease). (8) We have cloned the gene for a vitamin C transporter, which may be involved in neurodegenerative disease.