Calcium Channels and Hereditary Ataxia

这项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 通道是膜蛋白，在膜中起着至关重要的作用 兴奋性和触发突触传递。P/Q a亚基(A1a) 由CACNA1A基因编码的基因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(SCA6)。SCA6，a 常染色体显性遗传性进行性共济失调的形式与几乎选择性 浦肯野细胞变性，长期携带推测的致病突变 A1a信使核糖核酸的一个新的剪接体的C末端。这项研究建议 研究这种A1a亚基剪接形式的分布和 疾病归因于CAG重复扩增的致病性。 利用针对长剪接形式的抗血清，融合蛋白组成 长C末端和带有长尾的嵌合全长A1a亚基 无论有无扩大的CAG重复，我们都建议： 1)鉴定野生型和SCA6的分布和定位 P/Q型电压门控钙离子A1a亚基突变的长剪接形式 脑和转基因细胞中的通道及其与b亚基亚型的关系。 2)鉴定SCA6P/Q通道突变和b亚基的作用 P/Q通道动力学亚型及钙超载与钙偶联 小路。 3)用SCA6相关的聚谷氨酰胺培育表达A1a亚单位的小鼠 研究这些突变在骨质疏松症发生发展中的作用 转基因小鼠的共济失调和浦肯野细胞功能障碍。这些研究将 提供有关钙离子通道生物学的新信息，并可能有助于 了解SCA6中浦肯野细胞选择性易损性的基础。 在A1AC中鉴定延长的聚谷氨酰胺束的作用 特定的钙离子通道特性或浦肯野细胞活性的终点 将有助于阐明SCA6的发病机制，增加我们对SCA6的认识 P/Q型钙通道功能。

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.