Investigating the Mechanism of Prion Curing by [PSI+] No More Mutations

研究[PSI]不再突变治疗朊病毒的机制

• 批准号: 7545050
• 负责人: Susanne DiSalvo
• 金额: $ 2.68万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545050
• 关键词: Age; Alzheimer' s Disease; Biogenesis; Cell physiology; Complex; Disease; Ensure; Epigenetic Process; Event; Glean; Growth and Development function; In Vitro; Individual; Methods; Mutation; Nerve Degeneration; Numbers; Parkinson Disease; Pathway interactions; Prion Diseases; Prions; Process; Property; Protein Conformation; Protein Structure Initiative; Proteins; Quality Control; Rate; Saccharomyces cerevisiae; Saccharomycetales; Solubility; Structure; System; Testing; Therapeutic Intervention; Variant; Yeasts; age related; in vivo; insight; mutant; novel; protein misfolding; trait

DESCRIPTION (provided by applicant): The folding, localization, and solubility of proteins are basic processes, essential for proper cellular function as well as organismal growth and development; yet the quality control mechanisms that ensure faithful execution of these events become increasingly compromised with age. Not surprisingly, when these normal pathways of protein biogenesis go awry there can be devastating consequences. For example, the age related protein misfolding diseases, including Alzheimer's, Parkinson's and Huntingdon's diseases, as well as a set of unique prion diseases termed the transmissible spongiform encephalopathy's [1, 2] are each associated with severe neurodegeneration resulting from the self-perpetuated misfolding of a normal, host encoded protein. In healthy individuals, these proteins are soluble and functional, but in afflicted individuals, the same protein misfolds and forms highly structured aggregates which appear to act as templates for the continued misfolding of normal protein, thereby promoting their own assembly. The budding yeast Saccharomyces cerevisiae expresses several prion proteins that also partition between soluble and aggregated forms in an analogous, self-templated process. In these cases, however, the prion form of these proteins is not associated with disease but instead acts as an epigenetic agent to direct the inheritance of a novel trait [3]. Given the experimental tractability of yeast and the viability of the prion state, this system provides an invaluable platform with which to dissect the mechanisms underlying self-replicating changes in protein conformations in vivo. Detailed information on the cis sequence requirements for efficient prion propagation has been gleaned from a number of in vivo studies on the yeast prion protein Sup35. Several mutations in the prion domain of this factor dominantly interfere with efficient prion propagation by the wildtype protein, suggesting that these variants specifically target crucial steps in the process. To gain insight into these events, I propose to elucidate the mechanisms by which these variants eliminate the misfolded form through a combination of in vivo and in vitro analyses. Together, these studies will define the key properties that endow a protein with self-replicating character and by extension highlight potential points of therapeutic intervention for the mammalian protein misfolding diseases.

描述（由申请人提供）：蛋白质的折叠，定位和溶解度是基本过程，对于适当的细胞功能以及有机体生长和发育至关重要；然而，确保这些事件忠实执行的质量控制机制随着年龄的增长而变得越来越妥协。毫不奇怪，当这些蛋白质生物发生的正常途径出现问题时，可能会带来毁灭性的后果。例如，与年龄相关的蛋白质错误折叠疾病，包括阿尔茨海默氏症，帕金森氏症和亨廷顿疾病，以及一组称为可传播的脑病[1，2]的独特的疾病，每个疾病都与严重的神经变性有关，这与自我植入式构成的构成了一个正常的构造，这会导致严重的神经变性。在健康的个体中，这些蛋白质是可溶和功能的，但是在受苦的个体中，相同的蛋白质折叠率和形成高度结构化的聚集体，这些聚集体似乎是持续错误折叠正常蛋白的模板，从而促进了自己的组装。酿酒酵母的萌芽酵母糖含量表达了几种prion蛋白，这些蛋白也可以在类似的，自我绘制的过程中分配可溶性和聚合形式。然而，在这些情况下，这些蛋白质的prion形式与疾病无关，而是充当指导新特征的遗传的表观遗传剂[3]。鉴于酵母的实验性障碍和prion状态的生存能力，该系统提供了一个非常宝贵的平台，可以通过该平台解剖体内蛋白质构象的自我复制变化的机制。关于酵母菌prion蛋白sup35的许多体内研究，已经收集了有关有效prion传播的顺式序列要求的详细信息。该因素的prion域中的一些突变主要干扰了野生型蛋白的有效prion传播，这表明这些变体在此过程中特别针对关键步骤。为了深入了解这些事件，我建议阐明这些变体通过体内和体外分析的结合消除错误折叠形式的机制。总之，这些研究将定义具有自我复制特征的蛋白质的关键特性，并通过扩展突出了哺乳动物蛋白质折叠式疾病的治疗干预措施的潜在点。