Hsp40 and conformational disease

描述（由申请人提供）：构象疾病是神经退行性疾病，其中异常折叠蛋白质的淀粉样纤维形式的积累通过未知机制引起痴呆和细胞死亡。热休克蛋白40是分子伴侣，指导热休克蛋白70与疾病相关蛋白相互作用，并将它们分配在折叠、聚集和淀粉样蛋白形成的途径之间。朊病毒是一种感染性蛋白质，它组装成一种与神经变性相关的自我永久的淀粉样状态。对酵母朊病毒的研究提供了许多关于蛋白伴侣在淀粉样纤维形成中的功能的基本细节。在初步研究中，我们开发了许多检测方法来监测Hsp40在调节淀粉样蛋白形成和毒性中的作用。本文提出的研究旨在确定异常朊病毒生物合成导致细胞死亡的机制。此外，我们试图确定朊病毒组装的具体步骤，由不同的热休克蛋白40催化。最后，我们将确定的结构和功能特征的类型I和II Hsp40亚型，指定其行动朊病毒的生物发生。从这些研究中获得的数据将定义淀粉样蛋白形成中Hsp40功能的规则，并确定治疗构象疾病的治疗靶点。 构象性疾病是一种神经退行性疾病，其中异常折叠的蛋白质的淀粉样纤维形式的积累通过未知的机制引起痴呆和细胞死亡。从拟议的研究中获得的数据将定义Hsp40在调节淀粉样蛋白形成和毒性中的功能的规则，并确定用于治疗构象疾病的治疗靶点。

DESCRIPTION (provided by applicant): Conformational diseases are neurodegenerative maladies in which the accumulation of amyloid-like fibrillar forms of aberrantly folded proteins cause dementia and cell death via unknown mechanisms. Hsp40s are molecular chaperones that direct Hsp70 to interact with disease related proteins and partition them between pathways for folding, aggregation and amyloid formation. Prions are infectious proteins that that assemble into a self-perpetuating amyloid-like state that is associated with neurodegeneration. The study of yeast prions has provided many of the basic details about chaperone function in amyloid fibril formation. In preliminary studies we developed a number of assays to monitor Hsp40 action in modulating amyloid formation and toxicity. The studies proposed herein are designed to define mechanisms by which aberrant prion biogenesis causes cell death. In addition, we seek to identify the specific steps in prion assembly that are catalyzed by different Hsp40s. Finally, we will determine the structure and functional features of Type I and II Hsp40 sub-types that specify their action in prion biogenesis. The data obtained from these studies will define the rules for Hsp40 function in amyloid formation and identify therapeutic targets for the treatment of conformational disease. Conformational diseases are a neurodegenerative maladies in which the accumulation of amyloid-like fibrillar forms of aberrantly folded proteins cause deimentia and cell death via unknown mechanisms. The data obtained from the proposed studies will define the rules for Hsp40 function in modulation of amyloid formation and toxicity and identify therapeutic targets for the treatment of conformational disease.