Novel chaperones and neurodegeneration

摘要 多聚谷氨酰胺（polyQ）疾病是一类由9种神经退行性疾病引起的扩张性疾病 在特定蛋白质中的polyQ片段。polyQ束的扩张导致蛋白质聚集， 神经变性目前还没有治疗polyQ疾病的有效方法。一种潜在的治疗方法， polyQ疾病的治疗是减少polyQ聚集的策略的发展。有趣的是，我们和其他人 已经发现一种生物体盘基网柄藻（Dictyosteelium discoideum）天然地抵抗polyQ聚集。进一步工作 从我们的实验室鉴定了一种新的分子伴侣，我们命名为富含丝氨酸的伴侣蛋白1 （SRCP 1），其对于网骨藻对polyQ聚集的抗性是必需的，并且足以赋予 对polyQ聚集到其他生物体的抗性。在本申请中，我们提出1）确定分子量， SRCP 1用于识别polyQ扩增蛋白并抑制其聚集的机制; 2）确定 SRCP 1是否可以抑制亨廷顿病小鼠模型中的蛋白质聚集和行为缺陷; 和3）确定SRCP 1是否能够在脊髓小脑的小鼠模型中抑制polyQ聚集 共济失调3型。这些研究将共同确定SRCP 1抑制polyQ的机制 聚集，并确定SRCP 1是否具有预防或逆转小鼠模型中疾病表型的能力 PolyQ疾病。 !

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. !