Identification of therapeutic targets by genetic studies of neurodegeneration signal

泛素-蛋白酶体系统通过降解未折叠或错误折叠的蛋白质来控制蛋白质的质量，与神经退行性疾病的病因学密切相关。26S蛋白酶体由一个具有蛋白降解活性的核心颗粒(别名20S蛋白酶体)和一个或两个19S调节颗粒组成，分为LID和BASE亚复合体。在遗传功能增益筛选中，我们在果蝇疾病模型中发现LID亚基之一是扩大的聚谷氨酰胺诱导的神经退行性变表型的抑制因子。我们的结果表明，与年龄相关的26S蛋白酶体活性降低是迟发性神经变性风险增加的关键因素，并暗示通过提供过表达的LID亚单位来保持26S蛋白酶体的数量将提供一种延缓体内神经变性开始的方法。

The ubiquitin-proteasome system, which contributes to protein quality control by degrading unfolded or misfolded proteins, is closely related to the etiology of neurodegenerative disorders. The 26S proteasome is composed of one, proteolytically active, core particle (alias 20S proteasome) and one or two 19S regulatory particles subdivided into lid and base subcomplexes. In a genetic gain-of-function screen, we identified one of the lid subunits as a suppressor of expanded polyglutamine-induced neurodegenerative phenotypes in a Drosophila disease model. Our results suggest that an age-related reduction in 26S proteasome activity is the key factor of the increased risk for late-onset of neurodegeneration, and implicate that keeping the amount of the 26S proteasome by providing an overexpressed lid subunit will provide a way to delay the onset of neurodegeneration in vivo.