Novel chaperones and neurodegeneration

摘要 多聚谷氨酰胺(PolyQ)病是一类由扩张引起的九种神经退行性疾病 在特定蛋白质中的多聚Q区。多聚Q区的扩张导致蛋白质聚集和 神经退行性变。目前还没有治疗多发性精神分裂症的有效方法。一种潜在的治疗方法 多Q疾病是减少多Q聚集的策略的发展。有趣的是，我们和其他人 发现盘基网柄菌是一种天然抵抗多Q聚集的生物体。进一步工作 从我们实验室鉴定出一种新的分子伴侣，我们命名为富含丝氨酸的伴侣蛋白1 (SRCP1)，这既是网柄金藻抵抗多Q聚集所必需的，也足以传递 对其他生物的多聚Q聚集的抗性。在本申请中，我们建议1)确定分子 SRCP1识别多Q扩展蛋白并抑制其聚集的机制；2)确定 如果SRCP1可以抑制亨廷顿病小鼠模型中的蛋白质聚集和行为缺陷； 3)确定SRCP1是否能够抑制脊髓小脑小鼠模型的多聚体聚集 这些研究将共同确定SRCP1抑制PolyQ的机制 聚合并确定SRCP1是否有能力预防或逆转小鼠模型中的疾病表型 多Q病的症状。 好了！

Abstract The polyglutamine (polyQ) diseases are a class of nine neurodegenerative diseases caused by the expansion of a polyQ tract in specific proteins. Expansion of the polyQ tract results in protein aggregation and neurodegeneration. Currently there are no curative treatments for the polyQ diseases. One potential therapy for the polyQ diseases is the development of strategies to reduce polyQ aggregation. Interestingly we and others have found that one organism, Dictyostelium discoideum, is naturally resist to polyQ aggregation. Further work from our laboratory has identified a novel molecular chaperone we named serine rich chaperone protein 1 (SRCP1) that is both necessary for Dictyostelium’s resistance to polyQ aggregation and sufficient to impart resistance to polyQ aggregation to other organisms. In this application we propose to 1) determine the molecular mechanism SRCP1 utilizes to recognize polyQ expanded proteins and suppress their aggregation; 2) determine if SRCP1 can suppress protein aggregation and behavioral deficits in a mouse model of Huntington’s disease; and 3) determine if SRCP1 is capable of suppressing polyQ aggregation in a mouse model of Spinocerebellar ataxia type 3. Together these studies will determine the mechanism SRCP1 utilizes to suppress polyQ aggregation and determine if SRCP1 has the ability to prevent or reverse disease phenotypes in mouse models of polyQ disease. !