The polyglutamine expansion in spinocerebellar ataxia type 6 causes a β subunit-specific enhanced activation of P/Q-type calcium channels in Xenopus oocytes
The polyglutamine expansion in spinocerebellar ataxia type 6 causes a β subunit-specific enhanced activation of P/Q-type calcium channels in Xenopus oocytes
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DOI：
10.1523/jneurosci.20-17-06394.2000
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发表时间：
2000-09-01
影响因子：
5.3
通讯作者：
Gomez, CM
中科院分区：
文献类型：
--
作者：
Restituito, S;Thompson, RM;Gomez, CM
脊髓小脑共济失调 6 型 (SCA6) 是一种显性遗传的小脑退行性疾病，其特征是浦肯野细胞近乎选择性和进行性死亡。 SCA6 的潜在突变包括基因 CACNA1A 3' 区域中三核苷酸 CAG 重复的扩展，该基因编码神经元 P/Q 型电压门控钙通道的 α(1A) 亚基。尽管已知这种突变会导致某些 α(1A) 剪接形式中谷氨酰胺残基的扩展，但这些剪接形式的分布以及这种突变在 SCA6 中观察到的高度选择性浦肯野细胞变性中的作用尚未阐明。使用特定的抗血清，我们证明 SCA6 的病理扩张可能以 α(1A) 亚基的多种亚型表达，并且这些亚型在小脑中大量表达，特别是在浦肯野细胞体和树突中。使用表达SCA6突变的α(1A)亚基嵌合体，我们发现SCA6聚谷氨酰胺扩展仅在用β(4)亚基表达时改变通道激活和失活速率的电压依赖性，并损害P/Q通道的正常G蛋白调节。这些发现表明 SCA6 可能是一种通道病，并且 SCA6 的潜在突变通过钙离子的过度进入导致浦肯野细胞变性。
Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited degenerative disorder of the cerebellum characterized by nearly selective and progressive death of Purkinje cells. The underlying mutation in SCA6 consists of an expansion of a trinucleotide CAG repeat in the 3' region of the gene, CACNA1A, encoding the alpha(1A) subunit of the neuronal P/Q-type voltage-gated calcium channel. Although it is known that this mutation results in an expanded tract of glutamine residues in some alpha(1A) splice forms, the distribution of these splice forms and the role of this mutation in the highly selective Purkinje cell degeneration seen in SCA6 have yet to be elucidated. Using specific antisera we demonstrate that the pathological expansion in SCA6 can potentially be expressed in multiple isoforms of the alpha(1A) subunit, and that these isoforms are abundantly expressed in the cerebellum, particularly in the Purkinje cell bodies and dendrites. Using alpha(1A) subunit chimeras expressing SCA6 mutations, we show that the SCA6 polyglutamine expansion shifts the voltage dependence of channel activation and rate of inactivation only when expressed with beta(4) subunits and impairs normal G-protein regulation of P/Q channels. These findings suggest the possibility that SCA6 is a channelopathy, and that the underlying mutation in SCA6 causes Purkinje cell degeneration through excessive entry of calcium ions.