EXCEED THE SPACE PROVIDED. Polyglutamine repeat diseases comprise a family of progressive, neurodegenerative diseases that cause a variety of neurologic phenotypes, but that show a common, inexorable progression to neurologic dysfunction, and eventually, death. This family of diseases is caused by a common genetic mutation, the expansion of a CAG trinucleotide repeat that encodes a polyglutaminetract within the context of a variety of diverse proteins. One of these diseases, spinal and bulbar muscular atrophy (SBMA), is the only member of this group of diseases that causes a selective motor neuropathy. SBMA is an X-linked, adult-onset neurodegenerative disease that affects men with progressive muscle atrophy and weakness. The disease is caused by the expansion of a CAG trinucleotide repeat within the coding region of the androgen receptor gene, a member of the steroid/thyroid hormone receptor superfamily. Despite widespread neural and nonneural tissue expression of the androgen receptor, SBMA specifically affects motor neurons of the spinal cord and brainstem, with subclinical involvement of spinal sensory neurons as well. In addition to neuronal cell death, SBMA patients show the common neuropathological finding, found in nearly all polyglutamine repeat diseases, of abnormal protein aggregation, evidenced by neuronal intranuclear inclusions in affected neuronal tissues. Such evidence, combined with studies of several model systems (including those to be described in this proposal) indicate that expanded polyglutamine repeat-containing proteins are misfolded and targeted for degradation by the cell's protein degradation machinery. The goals of this proposal are to test hypotheses about 1) the role of AR ligand binding in the pathogenesis of SBMA, 2) the factors important for cell type specificity, and 3) the role of proteinmisfolding and molecular chaperone function in the pathogenesis of disease. To this end, we will create and characterize transgenic mouse models for SBMA. The development of an animal model for SBMA will allow the testing of PERFORMANCE SITE ========================================Section End===========================================
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