C. Elegans Model for Neurodegenerative Diseases of Aging

描述(申请人提供)：蛋白质折叠质量控制是一个与人类健康直接相关的内在重要生物学问题。随着人类寿命的延长，衰老引起的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稳态失衡是否是这些疾病的共同基础，我们开发了聚谷氨酰胺(PolyQ)病的线虫模型。我们的结果表明，多聚Q的聚集和毒性表现出对多聚Q长度的依赖，这种依赖可以被特定的伴侣和延长寿命的突变所抑制。然后，我们使用全基因组RNAi屏幕来识别调节多聚体聚集的五类遗传修饰物。基于这些结果，我们建议检验神经退行性疾病相关蛋白表现出共同的“蛋白毒性”的假设。这将通过建立在神经元和非神经元细胞中表达PolyQ蛋白、Huntingtin、ataxins 1和3、突变的SOD1和Prion的可比性转基因株来解决。这种综合的方法应该揭示基于细胞类型对蛋白质损伤的敏感性以及老化对聚集表型的影响的特征。该提案中的研究将涉及以下问题：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这一过程中的作用，以及包括影响受损蛋白质外观和命运的衰老在内的遗传修饰物的鉴定。这些研究的结果将解决不同的易于聚集的蛋白质是否会导致共同的“蛋白质毒性”，这些“蛋白质毒性”由蛋白质折叠质量控制“蛋白质组”的相同或不同成分调节。我们认为线虫提供了一个独特的机会来理解这些不同的过程是如何整合的，神经元细胞和非神经元细胞之间的差异的基础，以及受损蛋白质在动态平衡和衰老中的作用。

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.