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Identification of genes that modify ataxin-1-induced neurodegeneration

机译：鉴定修饰紫杉素-1诱导的神经变性的基因

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摘要

A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. 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 patho-genesis 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.
机译：越来越多的人类神经退行性疾病是由引起该疾病的蛋白质中的谷氨酰胺重复序列的扩增导致的。脊髓小脑共济失调1型（SCA1）是一种这样的疾病-由蛋白ataxin-1中的聚谷氨酰胺束的扩张引起。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SCA1基因，为SCA1建立了模型系统。在这里，我们表明，高水平的野生型紫杉素-1可以引起与由扩展蛋白引起的相似的变性表型。我们进行了基因筛选，以鉴定修饰SCA1诱导的神经变性的基因。几种修饰剂突出了蛋白质折叠和蛋白质清除在SCA1发育中的作用。此外，通过发现参与RNA加工，转录调控和细胞排毒的修饰剂，揭示了聚谷氨酰胺致病的新机制。这些发现可能与多谷氨酰胺疾病的治疗有关，也许与其他神经退行性疾病有关，例如阿尔茨海默氏病和帕金森氏病。

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