Novel chaperones and neurodegeneration

摘要 聚谷氨酰胺病是由CAG扩张引起的九种神经退行性疾病之一。 特定基因编码区的三核苷酸重复。这些扩展的CAG重复结果的翻译 在生产具有扩展的聚谷氨酰胺束的蛋白质时。含有这些膨胀的聚谷氨酰胺的蛋白质 神经束聚集并导致神经元毒性。因此，确定抑制的因素 聚谷氨酰胺聚集可能导致聚谷氨酰胺疾病的治疗方法的发展。在大多数 模型生物表达多谷氨酰胺重复序列会导致聚集，然而，我们发现 盘状网柄阿米巴自然表达数千个多谷氨酰胺重复序列 可溶的。此外，我们和其他人还发现，多谷氨酰胺扩大的亨廷顿蛋白外显子1的表达 在其他模式生物中聚集的构建物(MHTT)在Dictyostelius中保持可溶。这让我们找到了 假说网柄菌编码抑制多聚谷氨酰胺的新蛋白质和/或途径 聚合。为了确定抑制聚谷氨酰胺聚集的因素，我们进行了一项筛查和 发现了一个抑制网柄苔藓中多聚谷氨酰胺聚集的基因。此屏幕的一个警告 它是劳动密集型的，只覆盖了不到5%的基因组。要克服这一限制 费利西亚·威廉姆斯女士已经建立了一种新的筛查方案，可以实现几乎全基因组的饱和。她 将学习新的方法，获得技术专业知识，发表有影响力的研究成果，并为获得 博士后奖学金。总体而言，该项目将补充父母补助和正在进行的实验 实验室确定抑制聚谷氨酰胺聚集的新机制，并确定这些机制是否 可以转化为治疗。

Abstract The polyglutamine diseases are a class of nine neurodegenerative diseases caused by the expansion of a CAG trinucleotide repeat in the coding region of specific genes. Translation of these expanded CAG repeats results in the production of a protein with an expanded polyglutamine tract. Proteins with these expanded polyglutamine tracts aggregate and result in neuronal toxicity. Therefore, the identification of factors that suppress polyglutamine aggregation may lead to the development of therapies for the polyglutamine diseases. In most model organisms expression of a polyglutamine repeat results in aggregation, however, we have found that the social amoeba Dictyostelium discoideum naturally expresses thousands of polyglutamine repeats that remain soluble. Furthermore, we and others have found that expression of a polyglutamine expanded huntingtin exon 1 construct (mHtt) that aggregates in other model organisms remains soluble in Dictyostelium. This has led us to hypothesize that Dictyostelium encodes for novel proteins and/or pathways that suppresses polyglutamine aggregation. To identify factors that suppress polyglutamine aggregation we have carried out a screen and identified a single gene that suppresses polyglutamine aggregation in Dictyostelium. One caveat to this screen was that it was labor intensive and only covered less than five percent of the genome. To overcome this limitation Ms. Felicia Williams has established a new screening protocol that will allow near genome-wide saturation. She will learn new methodology, gain technical expertise, publish high impact research, and prepare herself to obtain a postdoctoral fellowship. Overall this project will complement the parental grant and ongoing experiments in the lab to identify novel mechanisms to suppress polyglutamine aggregation and determine if these mechanisms can be translated into therapies.