Role of sumoylation in aging

苏酰化在衰老中的作用

• 批准号: 9807523
• 负责人: Andrew Vaughn Samuelson
• 金额: $ 26.95万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807523
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Biological; Biological Models; Caenorhabditis elegans; Cell Lineage; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Clinical; Complex; Deposition; Deterioration; Development; Disease; Down-Regulation; Drops; Enzymes; Event; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heat-Shock Response; Histones; Human; Intervention; Late Onset Alzheimer Disease; Learning; Link; Longevity; Maintenance; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nuclear; Oxidative Stress; PRC1 Protein; Patients; Polycomb; Process; Proteins; Proteome; Resistance; Role; Single Nucleotide Polymorphism; Stem cells; Stress; Testing; Work; age related; biological adaptation to stress; chromatin remodeling; cohort; design; epigenome; healthy aging; heat shock transcription factor; improved; insight; isopeptidase; mature animal; normal aging; preservation; prevent; programs; protein misfolding; proteostasis; proteotoxicity; recruit; response; role model; transcription factor

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.

项目概要/摘要： 维持蛋白质组正常功能和折叠的机制（蛋白质稳态）在正常过程中下降。 衰老，这有助于神经退行性蛋白质错误折叠疾病的发作和进展，包括 老年痴呆症蛋白质组的功能完整性通过组合的 一组转录因子的作用，每个转录因子都对特定形式的蛋白毒性应激做出反应。期间 随着年龄的增长，这些反应下降，并最终导致蛋白质稳态的崩溃。C. elegans是一种优秀的 模型来研究这个复杂过程中所涉及的分子机制：特别是， 热休克反应，线粒体未折叠蛋白反应，ER未折叠蛋白反应，以及氧化应激反应。 应激反应都迅速下降，同时伴有蛋白质稳态下降早期迹象。为什么诱导 然而，对不同形式的蛋白毒性应激反应的下降知之甚少，但与 在应激位点形成抑制性染色质标记。我们已经确定了在老化过程中不适当的sumoylation 作为一种潜在的机制，以解释损失的压力反应诱导。这个项目将探讨如何改变 在衰老过程中sumoylation改变表观基因组，诱导应激反应，并维持 蛋白质稳态本提案的目的是确定衰老过程中类小泛素化的核变化， 获得机制洞察如何改变sumoylation交叉与染色质的变化，应激诱导 反应，以及对蛋白质稳态和寿命的影响。我们的中心假设是， 维持蛋白质稳态的应激反应程序下降，因为类小泛素化的增加导致蛋白质稳态的异常， 将染色质重塑复合物募集到应激位点。我们发现了一种与年龄相关的 在蛋白质稳定的转录调节因子的类小泛素化中，阻断类小泛素化可以防止蛋白质稳定的转录调节因子的类小泛素化。 成年动物的应激反应下调。相反，阻止去SUMO化会缩短寿命 并抑制基因表达值得注意的是，表达可以通过染色质修饰的失活来挽救。 酶，与年龄相关的sumoylation的变化与活性相关联的概念一致， 染色质重塑复合物目的1的核心是破译是否增加类小化在早期 C.线虫的衰老，与应激反应的急剧下降相一致，是导致衰老的原因。 蛋白质稳定和长寿。目标2集中在一个机制分析，以确定 类小泛素化、染色质重塑复合物和应激基因座染色质的变化。目标3的重点是 直接调节蛋白质稳定网络的转录因子本身， 这是它们在衰老过程中类小泛素化的功能后果。神经退行性疾病的许多致病因素 疾病是类小泛素化的，并且在AD中发现类小泛素化机制的核心组分中的突变 患者因此，阐明类小泛素化、染色质和蛋白质稳定网络之间的交叉点， 对神经退行性疾病的治疗和改善健康老龄化的努力具有意义。