C. elegans Model for Neurodegenerative Diseases of Aging

总结 蛋白质组的稳定性对所有生物合成过程的保真度至关重要， 对细胞的长期健康和生物体的寿命有很大的贡献。而 错误折叠蛋白质的表达是蛋白质生物发生的内在原因，受损蛋白质的积累 越来越多地被认为是衰老和年龄相关疾病的主要贡献者。我们有 表明，在应激和衰老反应中受损蛋白质的慢性表达具有破坏性， 蛋白质稳态（蛋白质稳态）的后果，导致一系列令人困惑的表型 影响几乎所有的生物过程。该基金的目的是了解蛋白质稳态的基础 衰老过程中的失调，以及这些事件如何增加疾病的风险。为了解决这个问题，我们将 研究如何表达疾病相关的，亚稳定的，聚集倾向的蛋白质在C。elegans 导致蛋白质稳定机制的崩溃，以及有效的细胞保护途径的作用， 它的平衡。这将在三个目标：1。衰老和疾病中蛋白质稳态的遗传学。我们 将采取系统的方法来确定调节疾病折叠稳定性的基因网络 相关的聚集倾向蛋白。这将通过在C. elegans来鉴定polyQ-扩增蛋白（雄激素受体，共济失调蛋白-3， 亨廷顿蛋白、突变SOD 1、A？和相关淀粉样蛋白ADan和ABri以及酵母朊病毒（Sup 35）。 这些筛选的比较分析将提供一个遗传基础，以确定共同的和独特的特点， 每一个易于聚集的蛋白质，以及蛋白质稳定网络的组成如何反映折叠 每种蛋白质的稳定性，2.衰老和疾病中蛋白质稳态的蛋白质组学。衰老和慢性 易聚集蛋白的表达干扰蛋白质稳态，这反过来又导致进一步的 当其他亚稳态蛋白质错误折叠时，蛋白质损伤的放大。我们提出了一种细胞的组合 生物学和蛋白质组学方法来识别面临衰老风险的不稳定蛋白质组， 蛋白毒性应激，和3.蛋白质稳态崩溃的细胞机制。我们的研究结果表明， 非天然蛋白质螯合分子伴侣，随着时间的推移，导致 分子伴侣依赖的细胞过程。由于分子伴侣在细胞浓度和细胞间变化， 组织类型，我们提出，伴侣隔离是一个促成因素，细胞功能障碍和组织 病理学并提出一种恢复年轻蛋白质静态状态的方法。

SUMMARY The stability of the proteome is of central importance to the fidelity of all biosynthetic processes, and contributes significantly to the long-term health of the cell and the lifespan of the organism. While the expression of misfolded proteins is intrinsic to protein biogenesis, the accumulation of damaged proteins has become increasingly recognized as a prominent contributor to aging and age-associated disease. We have shown that chronic expression of damaged proteins in response to stress and aging has devastating consequences on protein homeostasis (proteostasis), resulting in a bewildering collection of phenotypes affecting nearly all biological processes. The aims of this grant are to understand the basis of proteostasis dysregulation during aging, and how these events enhance the risk of disease. To address this, we will examine how the expression of disease associated, metastable, aggregation-prone proteins in C. elegans leads to the collapse of the proteostasis machinery, and the role of potent cytoprotective pathways to restore its balance. This will be presented in three aims: 1. The genetics of proteostasis in aging and disease. We will take a systems approach to identify the gene networks that regulate the folding stability of disease associated aggregation-prone proteins. This will be accomplished by genome-wide RNAi screens in C. elegans to identify the proteostasis network for polyQ-expansion proteins (Androgen Receptor, Ataxin-3, Huntingtin, mutant SOD1, A¿ and related amyloidogenic proteins ADan and ABri, and yeast prions (Sup35). Comparative analysis of these screens will provide a genetic basis to identify common and distinct features of each aggregation-prone protein and how the composition of the proteostasis network reflects the folding stability of each protein, 2. The proteomics of proteostasis in aging and disease. Aging and chronic expression of aggregation-prone proteins interfere with proteostasis, which in turn leads to a further amplification of protein damage as other metastable proteins misfold. We propose a combination of cell biological and proteomic approaches to identify the unstable proteome that is at risk in the face of aging and proteotoxic stress, and 3. Cellular mechanisms of proteostasis collapse. Our results suggest that damaged non-native proteins sequester molecular chaperones, which over time, results in the dysregulation of chaperone-dependent cellular processes. As chaperones vary in cellular concentration and among cell and tissue types, we propose that chaperone sequestration is a contributing factor to cellular dysfunction and tissue pathology and suggest an approach to restore the youthful proteostatic state.