Role of sumoylation in aging

项目摘要/摘要： 维持蛋白质组的正常功能和折叠的机制(蛋白稳定)在正常情况下下降 衰老，促进神经退行性蛋白错误折叠疾病的发生和发展，包括 阿尔茨海默氏症。蛋白质组的功能完整性通过组合保护免受压力 一组转录因子的作用，每个转录因子都准备对特定形式的蛋白毒性应激做出反应。在.期间 随着年龄的增长，这些反应会下降，并最终导致蛋白质平衡的崩溃。线虫是一种极好的 模型来研究这一复杂过程中涉及的分子机制：特别是 热休克反应、线粒体未折叠蛋白反应、内质网未折叠蛋白反应和氧化 应激反应都迅速下降，同时出现蛋白稳定性下降的早期迹象。为什么会有诱导性？ 然而，对于不同形式的蛋白毒性应激下降的反应，人们知之甚少，但与 应力部位形成抑制性染色质印记。我们发现了老化过程中不适当的相思甲基化。 作为一种潜在的机制来解释压力反应诱导性的丧失。这个项目将探索如何改变 在老化期间的总甲基化改变表观基因组、应激反应的诱导性和维持 蛋白质平衡。这项建议的目标是确定在老化和相思过程中的核变化。 从机制上洞察改变的总和是如何与染色质的变化相交的，即压力的诱导性 反应，以及对蛋白质抑制和寿命的影响。我们的中心假设是 维持蛋白稳定的应激反应程序下降，因为相加作用增加导致异常 染色质重塑复合体向应力部位的重新募集。我们发现了一个与年龄相关的增长 在蛋白质平衡的转录调节因子的总和作用中，阻断总和作用可阻止 成年动物应激反应的下调。相反，防止脱氢糖基化会缩短寿命 并抑制基因表达。值得注意的是，可以通过使染色质修饰失活来挽救表达 酶，与年龄相关的相思作用变化与酶活性有关的概念一致 染色质重塑复合体。目标1集中在破译早期是否增加相思 线虫的衰老与应激反应的急剧下降是下降的原因 蛋白质平衡和长寿。目标2以机械分析为中心，以确定 苏甲基化，染色质重塑复合体，以及应力部位染色质的变化。目标3的重点是 关于转录因子本身，它直接调节蛋白质平衡网络的组成部分，以及 它们在老化过程中苏莫化的功能后果。神经退行性变的许多致病因素 疾病是相加的，相加机制的核心成分在AD中被发现突变 病人。因此，阐明和甲基化、染色质和蛋白抑制网络之间的交集可能 对神经退行性疾病的治疗和改善健康老龄化的努力有影响。

Project Summary/Abstract: The mechanisms that maintain proper function and folding of the proteome (proteostasis) decline during normal aging, which facilitates the onset and progression of neurodegenerative protein misfolding diseases, including Alzheimer's Disease. The functional integrity of the proteome is safeguarded from stress through the combined action of a cohort of transcription factors, each primed to respond to specific forms of proteotoxic stress. During aging, these responses decline and ultimately precipitate a collapse of proteostasis. C. elegans is an excellent model to study the molecular mechanisms involved in this complex process: in particular, the inducibility of the heat shock response, mitochondrial unfolded protein response, ER unfolded protein response, and the oxidative stress response all rapidly decline concurrent with early signs of declining proteostasis. Why the inducibility in response to diverse forms of proteotoxic stress declines, however, is poorly understood, but coincides with the formation of repressive chromatin marks at stress loci. We have identified inappropriate sumoylation during aging as a potential mechanism to explain loss of stress response inducibility. This project will explore how changes in sumoylation during aging alter the epigenome, inducibility of stress responses, and maintenance of proteostasis. The objectives of this proposal are to identify nuclear changes in sumoylation during aging and gain mechanistic insight into how altered sumoylation intersects with changes in chromatin, inducibility of stress response, and the consequence on proteostasis and longevity. Our central hypothesis is that the inducibility of stress response programs maintaining proteostasis declines because increased sumoylation results in aberrant recruitment of chromatin remodeling complexes to stress loci. We have discovered an age-associated increase in sumoylation of a transcriptional regulator of proteostasis, and blocking sumoylation prevents the downregulation of stress response in adult animals. Conversely, preventing deSUMOylation shortens lifespan and represses gene expression. Notably, expression can be rescued by inactivation of chromatin modifying enzymes, consistent with the notion that age-related changes in sumoylation are linked to the activity of chromatin remodeling complexes. Aim 1 is centered on deciphering whether increasing sumoylation during early C. elegans aging, which coincides with the precipitous drop in stress response, is causative in declining proteostasis and longevity. Aim 2 centers on a mechanistic analysis to identify interconnections between sumoylation, chromatin remodeling complexes, and changes in chromatin at stress loci. The focus of Aim 3 is on the transcription factors themselves that directly regulate components of the proteostatic network and the functional consequence of their sumoylation during aging. Many of the causative factors of neurodegenerative diseases are sumoylated and mutations in core components of the sumoylation machinery are found in AD patients. Thus, elucidating the intersection between sumoylation, chromatin, and the proteostatic network may have implications for the treatment of neurodegenerative disease and efforts to improve healthy aging.