Dietary restriction and proteasome-mediated protein degradation in the aging CNS

描述(申请人提供)：蛋白酶体是一种细胞内的蛋白水解酶，负责大量的细胞内蛋白分解。在大多数组织中，抑制蛋白酶体-蛋白分解途径被认为是正常衰老的一部分。蛋白酶体抑制可能导致蛋白质组中许多与年龄相关的变化，从而在衰老过程中促进各种细胞紊乱，尽管缺乏严格的生化和蛋白质组学分析使这种估计在很大程度上是假设和理论的。限制饮食(DR)延长哺乳动物的平均和最长寿命，并在细胞和系统水平上抑制各种有害的与年龄相关的变化。我们的数据表明，DR改善了与年龄相关的中枢神经系统(CNS)内蛋白酶体功能的损害。这项提议的重点是验证这样一个假设，即DR改善了中枢神经系统蛋白酶体功能中与年龄相关的损害，这是直接影响蛋白酶体复合体的结果。此外，我们假设DR对蛋白水解酶的这种保护有助于维持蛋白质组并抑制中枢神经系统老化过程中的细胞干扰。其具体目的如下：(1)检验DR改变CNS选择性区域蛋白酶体复合体的生物发生、组成和氧化中与年龄相关的改变的假说；(2)检验DR改变CNS选择性区域蛋白酶体功能与年龄相关的改变的假说；(3)确定蛋白酶体抑制后CNS中哪些蛋白质的降解减少；(4)检验DR改善CNS内关键蛋白酶体底物中与年龄相关的升高的假说。综上所述，这些数据将有助于我们理解中枢神经系统中DR诱导效应的分子基础，并有助于我们理解DR如何改善中枢神经系统中与年龄相关的蛋白酶体功能损害。此外，这些数据将有助于我们理解蛋白酶体抑制如何促进蛋白质组的破坏，并最终导致中枢神经系统的细胞功能障碍。这些数据可能不仅对我们理解中枢神经系统的衰老很重要，而且可能为衰老和中枢神经系统衰老相关疾病确定新的治疗靶点。

DESCRIPTION (provided by applicant): The proteasome is an intracellular protease that is responsible for a significant amount of intracellular proteolysis. Inhibition of the proteasome-proteolytic pathway is thought to occur as a part of normal aging in most tissues. Proteasome inhibition likely contributes to numerous age-related alterations in the proteome, and thereby promotes a variety of cell disturbances during aging, although the lack of rigorous biochemical and proteomic analysis has made such estimations largely hypothetical and theoretical. Dietary restriction (DR) increases average and maximal lifespan in mammals, and suppresses a variety of deleterious age-related alterations at both the cellular and systems level. Our data suggests that DR ameliorates age-related impairments in proteasome function within the central nervous system (CNS). The focus of this proposal is to test the hypothesis that DR ameliorates age-related impairments in proteasome function in the CNS, as the result of direct effects on the proteasome complex. Additionally, we hypothesize that this preservation of proteolysis by DR contributes to maintenance of the proteome and inhibition of cellular disturbances during aging of the CNS. The specific aims are as follows: (1) to test the hypothesis that DR alters age-related alterations in the biogenesis, composition, and oxidation of proteasome complexes in selective regions of the CNS; (2) to test the hypothesis that DR alters age-related changes in proteasome function in selective regions of the CNS; (3) to identify which proteins in the CNS exhibit decreased degradation following proteasome inhibition; (4) to test the hypothesis that DR ameliorates age-related elevations in key proteasome substrates within the CNS. Together, these data will significantly contribute to our understanding of the molecular basis for DR-induced effects in the CNS, and contribute to our understanding of how DR ameliorates age-related impairments in proteasome function in the CNS. Additionally, these data will contribute to our understanding of how proteasome inhibition promotes disruptions in the proteome, and ultimately contributes to cellular dysfunction in the CNS. Such data may not only be important to our understanding of aging in the CNS, but may identify novel therapeutic targets for aging and age-related diseases of the CNS.