Identification of genes that modify ataxin-1-induced neurodegeneration
Identification of genes that modify ataxin-1-induced neurodegeneration
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DOI：
10.1038/35040584
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发表时间：
2000-11-02
期刊：
影响因子：
64.8
通讯作者：
Botas, J
中科院分区：
文献类型：
--
作者：
Fernandez-Funez, P;Nino-Rosales, ML;Botas, J
越来越多的人类神经退行性疾病是由引起疾病的蛋白质中谷氨酰胺重复序列的扩展引起的(1)。脊髓小脑性共济失调 1 型 (SCA1) 就是这样一种疾病，由蛋白质 ataxin-1 中的聚谷氨酰胺束扩张引起。为了阐明这组疾病中神经元变性的遗传途径和分子机制，我们通过在果蝇中表达全长人类 SCA1 基因，创建了 SCA1 模型系统。在这里，我们表明，高水平的野生型 ataxin-1 可导致与扩增蛋白所引起的退化表型类似的退化表型。我们进行了基因筛选，以确定修饰 SCA1 诱导的神经变性的基因。一些修饰物强调了蛋白质折叠和蛋白质清除在 SCA1 发育中的作用。此外，参与RNA加工、转录调节和细胞解毒的修饰剂的发现揭示了多聚谷氨酰胺发病机制的新机制。这些发现可能与多聚谷氨酰胺疾病的治疗有关，也可能与其他神经退行性疾病有关，例如阿尔茨海默病和帕金森病。
A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease(1). Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.