PATHOGENESIS STUDIES OF SPINOCEREBELLAR ATAXIA TYPE 6

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DESCRIPTION (from Abstract): Recently, we made the discovery that Spinocerebellar ataxia type 6 (SCA6) is caused by a small polyglutamine tract expansion in the human (IA voltage gated calcium channel. SCA6 is an autosomal dominant late onset progressive ataxia leading to permanent cerebellar and brain stem dysfunction. In normal individuals, the number of polyglutamine tracts present in a IA voltage gated calcium channel ranges from 4 to 16 repeat units. In SCA6 patients, this number of repeat units can range from 21 to 27. Compared to other known polyglutamine diseases like SCA 1, SCA2, SCA3, SMBA, DRPLA and HD, the expanded mutant alleles in SCA6 (21-27 repeats) are remarkably smaller than the expanded alleles seen in any of the other neurodegenerative diseases (36-121 repeats) and are well within the normal range of polyglutamine tracts seen at the other loci in many unaffected individuals. We are interested in understanding the pathogenesis of cerebellar degeneration in SCA6. We propose to carry out in vivo studies using transgenic mouse models to determine the effect of polyglutamine expansion on (I A voltage gated Ca2+ channel function. Phenotype and pathological examination is proposed to analyze the effect of the transgene on cerebellar degeneration. Evaluation of (IA Ca2+ channel activities in brain slices and cells obtained from cerebellar of the transgenic mice is proposed. In vitro studies using Xenopus oocytes are proposed to address the effect of the polyglutamine tract length on the electrophysiologic properties of the (IA Ca2+ channel subunit. Families that demonstrate linkage to chromosome 19p13 will be analyzed for expansion as well as other mutations in the channel. The results obtained from the proposed studies will provide answers to the role of polyglutamine expansion in neuronal cell death leading to SCA6.