Dissecting the aging-associated decline in cellular proteostasis - Project 1

项目1-Frydman-剖析与衰老相关的细胞蛋白稳定性下降 项目总结： 通过保持蛋白质内稳态或蛋白质稳态来维持功能蛋白质组的能力是必不可少的。 为了细胞的存活。然而，这种能力在衰老过程中会下降。蛋白质平衡的这种崩溃导致了 错误折叠和聚集的蛋白质积累是迟发性疾病的标志，包括， 最值得注意的是，包括阿尔茨海默氏症、帕金森氏症和亨廷顿氏症在内的一系列神经退行性疾病 疾病。然而，在很大程度上还不清楚是什么细胞变化导致了蛋白质的丢失。 动态平衡和衰老过程中受损蛋白质的积累。我们建议定义这些机制 为了更好地理解细胞干预可以 改善衰老过程，改善衰老相关疾病。 蛋白质的稳定是通过分子伴侣的相互作用来维持的，分子伴侣对蛋白质来说是必不可少的。 折叠和功能，以及质量控制因素，包括泛素-蛋白酶体系统和自噬， 以错误折叠的蛋白质为靶标进行消除。越来越多的证据表明，蛋白质平衡 在衰老过程中会被破坏。然而，我们对衰老如何改变蛋白平衡调节器的相互作用的理解是 这还远远没有完成。该项目将研究调节蛋白质生命周期的几个阶段，包括 翻译保真度、伴侣功能和错误折叠的蛋白质管理，以确定什么细胞 变化决定了与衰老相关的广泛的蛋白质平衡崩溃。重要的是，我们将研究如何 聚集性疾病相关蛋白的存在，如A-β、tau和多聚Q扩展的Huntingtin 外显子1影响蛋白平衡功能障碍和衰老之间的相互作用。这将提供对以下方面的实质性见解 这些过程的年龄依赖性调节如何可能有助于蛋白质稳定性的下降 相关的细胞活性下降，这是衰老和几个晚发性人类的主要标志 神经退行性疾病。 为了在分子水平上阐明衰老如何影响新翻译蛋白质的折叠和 管理错误折叠和应激变性的蛋白质，我们计划利用我们的集体专业知识 衰老模型的多样性：(I)研究衰老如何影响新造生物的生物发生和折叠 蛋白质和(2)决定年龄如何影响错误折叠和容易聚集的管理 蛋白质类

Project 1 – Frydman - Dissecting the aging-associated decline in cellular proteostasis Project Summary: The ability to maintain a functional proteome by preserving protein homeostasis, or proteostasis, is essential for cell viability. Yet, this ability declines during the process of aging. Such a collapse in proteostasis results in the accumulation of misfolded and aggregated proteins that are a hallmark of late-onset diseases including, most notably, a wide range of neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s Diseases. However, it remains largely unknown what cellular changes are responsible for the loss of protein homeostasis and the accumulation of damaged proteins during aging. We propose to define the mechanisms and consequences of this proteostasis decline in order to better understand what cellular interventions could improve the aging process and ameliorate age-related diseases. Proteostasis is maintained through the interplay of molecular chaperones, which are essential for protein folding and function, and quality control factors, including the ubiquitin-proteasome system and autophagy, which target misfolded proteins for elimination. Accumulating evidence suggests that the proteostasis balance is disrupted during aging. Yet, our understanding of how aging alters the interplay of proteostasis regulators is far from complete. This Project will examine several phases that regulate the life cycle of a protein, including translational fidelity, chaperone function, and misfolded protein management, to determine what cellular changes dictate the widespread proteostasis collapse associated with aging. Importantly, we will examine how the presence of aggregation-prone disease-linked proteins such as A-beta, tau and polyQ-expanded Huntingtin exon1 affect the interplay between proteostasis disfunction and aging. This will provide substantial insight into how age-dependent modulation of these processes might contribute to the decline in proteostasis, and associated decline in cell viability, that is a primary hallmark of aging and several late-onset human neurodegenerative diseases. In order to elucidate at a molecular level how aging affects the folding of newly translated proteins and the management of misfolded and stress-denatured proteins, we plan to exploit our collective expertise across a variety of models of aging to: (i) Examine how aging affects biogenesis and folding of newly made proteins and (ii) Determine how aging affects the management of misfolded and aggregation-prone proteins