Calcium Channels and Hereditary Ataxia

本研究的长期目标是确定P/Q型的作用 浦肯野细胞变性和遗传性共济失调中的电压门控通道。P/Q 通道是在细胞膜上起关键作用的膜蛋白， 兴奋性和触发突触传递。P/Q a亚基（a1 A） 由基因CACNA 1A编码，与家族性偏头痛有关， 遗传性发作性共济失调和脊髓小脑性共济失调6型（SCA 6）。SCA6，a 一种常染色体显性进行性共济失调，与近选择性 浦肯野细胞变性，在长时间的 一种新的剪接形式的α 1A mRNA的C末端。本研究建议， 研究这种a1 A亚基剪接形式的分布， 疾病所归因的CAG重复扩增的致病性。 使用对长剪接形式特异的抗血清， 长C末端和带有长尾的嵌合全长α 1 A亚基 有和没有扩展的CAG重复序列，我们建议： 1)表征野生型和SCA 6的分布和定位 P/Q型电压门控Ca ~（2+）α 1A亚基的突变长剪接形式 脑和转染细胞中的通道以及与B亚单位亚型的关系。 2)表征SCA 6 P/Q通道突变和B亚基的作用 亚型对P/Q通道动力学的影响，以及对钙超载和钙偶联的影响。 途径。 3)培养表达具有SCA 6相关多聚谷氨酰胺的a1 A亚基的小鼠 扩大调查的作用，这些突变的发展， 共济失调和浦肯野细胞功能障碍。这些研究将 提供有关Ca+2通道生物学的新信息，并可能有助于 理解SCA 6中浦肯野细胞选择性脆弱性的基础。 在a1 A C中鉴定延长的多聚谷氨酰胺束的作用 对特异性Ca+2通道特性或浦肯野细胞活力的影响 这将有助于阐明SCA 6的发病机制，并增加我们对 P/Q型Ca+2通道功能。

The longterm objective of this study is to define the role of the P/Q-type voltage-gated channel in Purkinje-cell degeneration and hereditary ataxia. P/Q channels are membrane proteins that play a crucial role in membrane excitability and triggering synaptic transmission. The P/Q a subunit (a1A) encoded by the gene, CACNA1A, has been implicated in familial migraine, hereditary episodic ataxia and spinocerebellar ataxia type 6 (SCA6). SCA6, a form of autosomal dominant progressive ataxia associated with nearly selective Purkinje cell degeneration, bears the putative pathogenic mutation in the long C terminus of a novel spliceform of the a1A mRNA. This study proposes to investigate the distribution of this a1A subunit spliceform and the pathogenicity of the CAG repeat expansion to which the disease is attributed. Using antisera specific for the long splice form, fusion proteins composed of the long C terminus and chimeric full length a1A subunits bearing the long tail with and without expanded CAG repeats we propose to: 1) Characterize the distribution and localization of the wild type and SCA6 mutant long splice form of the a1A subunit of the P/Q-type voltage-gated Ca2+ channel in brain and transfected cells and in relation to b subunit subtypes. 2) Characterize the effect of the SCA6 P/Q channel mutation and b subunit subtype on P/Q channel kinetics, and on Ca2+ overload and calcium-coupled pathways. 3) Develop mice that express the a1A subunit with SCA6-associated polyglutamine expansions to investigate the role of these mutations in the development of ataxia and Purkinje cell dysfunction in transgenic mice. These studies will provide new information about the biology of Ca+2 channels and may aid in understanding the basis for selective vulnerability of Purkinje cells in SCA6. Identification of an effect of an elongated polyglutamine tract in the a1A C terminus on specific Ca+2 channel properties or on Purkinje cell viability would help elucidate the pathogenesis of SCA6 and increase our understanding of P/Q-type Ca+2 channel function.