X LINKED SPINAL AND BULBAR MUSCULAR ATROPHY

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X-linked spinal and bulbar muscular atrophy (SBMA), a form of motor neuron disease, is one of a growing list of disorders caused by expanded trinucleotide repeats. The mutation in SBMA is enlargement of a CAG repeat in the first exon of the androgen receptor gene. This CAG repeat encodes a polyglutamine tract near the amino end of the receptor protein, which is similar to repeats found in other proteins involved in control of transcription and development. A very similar repeat alteration has recently been found in Huntington's disease. Enlargement of CAG/polyglutamine tracts may thus be an important cause of neurodegenerative disease. We plan to characterize the causal connection between the androgen receptor mutations and the motor neuron degeneration of SBMA by studying the effects of the mutant androgen receptor in cultured neurons and transgenic mice. Constructs with normal and expanded versions of the androgen receptor will be assayed for neurotoxicity in vitro and in vivo. Since the normal function of the androgen receptor protein is as a transcription factor, and the disease is likely caused by a toxic gain of function of the receptor protein, the probable mechanism of neurotoxicity is through altered transcriptional regulation of one or more target genes. We plan to identify target genes that are aberrantly regulated by the expanded androgen receptor of SBMA and to look for specific effects of the altered receptor on genes known to play a role in motor neuron survival. We expect that our results will increase understanding of the cell biology of motor neurons and steroid hormone receptors. This project should also elucidate the pathogenesis of SBMA and may lead to effective treatment for this and other hereditary degenerative neurological disorders.