PATHOGENESIS STUDIES OF SPINOCEREBELLAR ATAXIA TYPE 6

摘要：最近，我们发现， 脊髓小脑性共济失调6型（SCA 6）是由一个小的多聚谷氨酰胺束引起的 人体中的扩张（IA电压门控钙通道。SCA 6是一个常染色体 显性迟发性进行性共济失调导致永久性小脑和 脑干功能障碍在正常个体中，多聚谷氨酰胺的数量 IA电压门控钙通道中存在的束的范围为4至16个重复 单位在SCA 6患者中，重复单位的数量范围为21至27。 与其他已知的多聚谷氨酰胺疾病如SCA 1、SCA 2、SCA 3、SMBA相比， SCA 6中扩增的突变等位基因DRPLA和HD（21-27个重复）是 明显小于在其他任何一个中看到的扩展等位基因， 神经退行性疾病（36-121个重复），并且在正常范围内 在许多未受影响的人中，在其他位点观察到一系列多聚谷氨酰胺束， 个体我们有兴趣了解小脑的发病机制， SCA 6中的退化。我们建议使用转基因技术进行体内研究， 小鼠模型以确定多聚谷氨酰胺扩增对（I A）电压的影响 门控钙通道功能。建议进行表型和病理学检查 分析转基因对小脑退化的影响。评价 在脑切片和细胞中的（IA）Ca 2+通道活性， 小脑的转基因小鼠的建议。使用非洲爪蟾的体外研究 卵母细胞被提议解决多聚谷氨酰胺束长度对 （IA）Ca ~（2+）通道亚单位的电生理特性。家庭 将分析证明与染色体19 p13连锁的基因的扩增， 以及通道中的其他突变。从建议的结果 研究将为多聚谷氨酰胺扩增在神经元中的作用提供答案。 细胞死亡导致SCA 6。

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.