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Role of sumoylation in aging

苏酰化在衰老中的作用

基本信息

批准号：
9981595
负责人：
Andrew Vaughn Samuelson
金额：
$ 15.4万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981595
关键词：
Adult Affect Age Aging Alzheimer&apos 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 Estrogen receptor positive 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 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 stem cells transcription factor

项目摘要

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.

项目总结/文摘:

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HSF-1: Guardian of the Proteome Through Integration of Longevity Signals to the Proteostatic Network.

DOI：
10.3389/fragi.2022.861686
发表时间：
2022
期刊：
FRONTIERS IN AGING
影响因子：
0
作者：
Lazaro-Pena, Maria I.;Ward, Zachary C.;Yang, Sifan;Strohm, Alexandra;Merrill, Alyssa K.;Soto, Celia A.;Samuelson, Andrew V.
通讯作者：
Samuelson, Andrew V.

Quantifying Tissue-Specific Proteostatic Decline in Caenorhabditis elegans.