C. Elegans Model for Neurodegenerative Diseases of Aging

描述（由申请人提供）：蛋白质折叠质量控制是一个本质上重要的生物学问题，与人类健康直接相关。随着人类寿命的增加，神经退行性疾病的风险增加，其中许多与错误折叠和受损蛋白质的表达有关。为了检验这种蛋白质内稳态的不平衡是否是这些疾病的共同基础，我们开发了一种C。多聚谷氨酰胺（polyQ）疾病的线虫模型。我们的研究结果表明，polyQ聚集和毒性表现出依赖于polyQ的长度，可以抑制特定的伴侣和突变，提高寿命。然后，我们使用全基因组RNAi筛选来鉴定调节polyQ聚集的五类遗传修饰剂。基于这些结果，我们建议测试的假设，神经退行性疾病相关蛋白表现出共同的“蛋白毒性”。这将通过在神经元和非神经元细胞中建立表达polyQ蛋白、亨廷顿蛋白、共济失调蛋白1和3、突变体SOD 1和朊病毒的可比较的转基因系来解决。这种全面的方法应揭示功能的基础上的细胞类型的敏感性蛋白质损伤和老化的影响聚集表型。本提案中的研究将解决导致错误折叠物种和聚集体出现的生化事件，蛋白质错误折叠的分子事件和细胞后果，伴侣网络和蛋白酶体在此过程中的作用，以及识别影响受损蛋白质外观和命运的遗传修饰剂，包括衰老。这些研究的结果将解决不同的聚集倾向的蛋白质是否会导致共同的“蛋白毒性”，这是由相同或不同的蛋白质折叠质量控制“蛋白质组”的组成部分。我们建议C.线虫提供了一个独特的机会，了解这些不同的过程是如何整合的，神经元和非神经元细胞之间的差异的基础，以及受损蛋白质对稳态和衰老的作用。

DESCRIPTION (provided by applicant): Protein folding quality control is an inherently important biological problem with immediate relevance to human health. With increased human lifespan is the increased risk of neurodegenerative diseases of aging many of which are associated with the expression of misfolded and damaged proteins. To examine whether this imbalance in protein homeostasis is a common basis for these diseases, we developed a C. elegans model for polyglutamine (polyQ) disease. Our results show that polyQ aggregation and toxicity exhibit a dependence on polyQ-length that can be suppressed by specific chaperones and mutations that enhance longevity. We then used a genome-wide RNAi screen to identify five classes of genetic modifiers that regulate polyQ aggregation. Based on these results, we propose to test the hypothesis that neurodegenerative disease-associated proteins exhibit a common "proteotoxicity". This will be addressed by establishing comparable transgenic lines expressing polyQ proteins, Huntingtin, Ataxins 1 and 3, mutant SOD1, and prions in neurons and non-neuronal cells. This comprehensive approach should reveal features on the basis of cell-type sensitivity of protein damage and the effects of aging on the aggregation phenotype. The studies in this proposal will address questions on the biochemical events that lead to the appearance of misfolded species and aggregates, the molecular events and cellular consequences of protein misfolding, the role of chaperone networks and the proteasome in this process, and identification of genetic modifiers including aging that influences the appearance and fate of damaged proteins. The outcome of these studies will address whether distinct aggregation-prone proteins result in a common "proteotoxicity" that are regulated by the same or distinct components of the protein folding quality control "proteome". We propose that C. elegans offers a unique opportunity to understand how these various processes are integrated, the basis for differences between neuronal and non-neuronal cells, and the role of damaged proteins on homeostasis and aging.