PATHOGENESIS STUDIES OF SPINOCEREBELLAR ATAXIA TYPE 6

描述(摘自摘要)：最近，我们发现 脊髓小脑性共济失调6型(SCA6)是由小的聚谷氨酰胺束引起的 在人体内扩张(IA电压门控钙通道。SCA6是常染色体 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。在正常人中，多聚谷氨酰胺的数量 IA电压门控钙通道中存在从4个到16个重复的束 单位。在SCA6患者中，重复单位的数量从21到27个不等。 与其他已知的聚谷氨酰胺疾病如SCA1、SCA2、SCA3、SMBA、 SCA6(重复21-27次)的扩展突变等位基因DRPLA和HD为 显著小于在其他任何一种情况下看到的扩展等位基因 神经退行性疾病(36-121个重复)，在正常范围内 在许多未受影响的人群中，在其他基因座上看到的聚谷氨酰胺束的范围 个人。我们对了解小脑的发病机制很感兴趣。 SCA6退行性变。我们建议使用转基因技术进行体内研究 测定聚谷氨酰胺扩张对(I A)电压影响的小鼠模型 门控钙通道功能。建议进行表型和病理检查。 分析转基因对小脑退行性变的影响。评估 获得的脑片和细胞的(IA)钙通道活性 提出了转基因小鼠的小脑移植模型。非洲爪哇的体外研究 卵母细胞的提出是为了解决聚谷氨酰胺束长度对 (IA钙通道亚基)的电生理特性。家庭 证明与染色体19p13连锁的基因将被分析为 以及通道中的其他突变。建议的研究结果： 研究将为聚谷氨酰胺在神经细胞中的作用提供答案 细胞死亡导致SCA6。

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.