Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions
Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions
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DOI：
10.1093/hmg/10.11.1201
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发表时间：
2001-05-15
影响因子：
3.5
通讯作者：
Brice, A
中科院分区：
文献类型：
--
作者：
Lebre, AS;Jamot, L;Brice, A
脊髓小脑性共济失调7 （SCA7）是一种由CAG重复序列在SCA7基因编码区扩增引起的神经退行性疾病。这种疾病主要影响小脑和视网膜，但随着疾病的进展，也会影响许多其他中枢神经系统（CNS）结构。Ataxin-7由SCA7基因编码，是一种在包括中枢神经系统在内的许多组织中表达的功能未知的蛋白。在正常大脑中，Ataxin-7存在于神经元的细胞质和/或细胞核中，但在SCA7脑中，Ataxin-7积聚在核内包涵体中。Ataxin-7普遍表达，但突变只会导致大脑某些区域的神经元死亡。这种选择性退行性变的模式可能是通过在脆弱细胞中特异性表达的伴侣相互作用来解释的。采用双杂交方法筛选人视网膜cDNA文库中ataxin-7结合蛋白，分离出ccl -associated protein （CAP）的剪接变体R85， R85和CAP是由定位于染色体10q23-q24上的SH3P12基因交替剪接产生的，通过拉下和共免疫沉淀证实了ataxin-7与SH3P12基因产物（SH3P12GPs）的相互作用。SH3P12GPs在小脑浦肯野细胞中表达。Ataxin-7在共转染的Cos-7细胞中与全长R85 （R85FL）共定位，并在SCA7患者脑内神经元核内包涵体中与SH3P12GPs之一共定位。我们认为这种相互作用是与ataxin-7的功能或转换相关的生理途径的一部分，并讨论了其在SCA7疾病病理生理过程中的作用。
Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by expansion of a CAG repeat in the coding region of the SCA7 gene. The disease primarily affects the cerebellum and the retina, but also many other central nervous system (CNS) structures as the disease progresses. Ataxin-7, encoded by the SCA7 gene, is a protein of unknown function expressed in many tissues including the CNS, In normal brain, ataxin-7 is found in the cytoplasm and/or nucleus of neurons, but in SCA7 brain ataxin-7 accumulates in intranuclear inclusions. Ataxin-7 is expressed ubiquitously, but mutation leads to neuronal death in only certain areas of the brain. This selective pattern of degeneration might be explained by interaction with a partner that is specifically expressed in vulnerable cells. We used a two-hybrid approach to screen a human retina cDNA library for ataxin-7-binding proteins, and isolated R85, a splice variant of Cbl-associated protein (CAP), R85 and CAP are generated by alternative splicing of the gene SH3P12 which we localized on chromosome 10q23-q24, The interaction between ataxin-7 and the SH3P12 gene products (SH3P12GPs) was confirmed by pull-down and coimmunoprecipitation. SH3P12GPs are expressed in Purkinje cells in the cerebellum. Ataxin-7 colocalizes with full-length R85 (R85FL) in co-transfected Cos-7 cells and with one of the SH3P12GPs in neuronal intranuclear inclusions in brain from a SCA7 patient. We propose that this interaction is part of a physiological pathway related to the function or turnover of ataxin-7, Its role in the pathophysiological process of SCA7 disease is discussed.