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Unique ubiquitin processes in misfolded protein diseases of the nervous system

神经系统错误折叠蛋白疾病中独特的泛素过程

基本信息

批准号：
10284055
负责人：
Sokol Todi
金额：
$ 34.65万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284055
关键词：
Adopted Age Alzheimer&apos s Disease Amyloid beta-Protein Attention Biochemical Biological Assay Biology Cell physiology Cells Chemicals Cleaved cell Clinical Complex Data Degenerative Disorder Degradation Pathway Development Disease Disease model Drosophila genus Drosophila inturned protein Drosophila melanogaster Enzymes Eye Family Funding Mechanisms Genetic Screening Health Homeostasis Individual Intervention Investigation Lead Length Light Longevity Mammalian Cell Mass Spectrum Analysis Monitor Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Neurosciences Outcome Parkinson Disease Pathway interactions Patients Performance Phenotype Physiological Polymers Polyubiquitin Population Prion Diseases Process Protein Array Proteins Publishing Role Sclerosis Stress Structure Testing Toxic effect Transgenic Organisms Ubiquitin Ubiquitination Work age related age related neurodegeneration alpha synuclein biochemical tools cell growth regulation cell motility chemical conjugate developmental toxicity fighting fly in vivo insight misfolded protein monomer multicatalytic endopeptidase complex nervous system disorder neurotoxic novel novel therapeutics polyglutamine premature protein expression response tau Proteins tau mutation tool

项目摘要

Age-related diseases of the nervous system are diverse and will continue to grow in importance as the population ages. So far, the most impactful among them have eluded successful clinical intervention; therefore, their investigation constitutes a clear need in the field of neuroscience. Among these diseases are Alzheimer's, Parkinson's and the polyglutamine family of disorders, caused by the presence, accumulation and aggregation of misfolded proteins. Ground-breaking work has dissected how cells coordinate responses to delay or suppress misfolded protein toxicity, yet neurons ultimately succumb to these proteins and diseases progress. Among processes involved in maintaining neuronal homeostasis in the face of misfolded proteins are refolding and degradation pathways. Key to these processes is the small modifier protein, ubiquitin. Here, we seek to investigate an aspect of ubiquitin that has eluded exploration in neurodegeneration: unanchored, or free, ubiquitin chains and their impact on misfolded protein toxicity. Ubiquitin is best known for targeting substrates for proteasomal degradation by being chemically tethered onto them. Ubiquitin exists in numerous types of configurations, including chains that can adopt a wide array of topological complexities and length, and that coordinate downstream substrate recognition and processing. Among the types of poly-ubiquitin chains are unanchored species that are not attached onto other proteins. We recently published evidence on the presence, function, utilization and processing of these chains in vivo. Among the most intriguing findings was the observation that free ubiquitin chains can be conjugated onto substrates en bloc, without the need to be first dismantled into monomers. This novel finding led us to wonder whether it may be beneficial for cells under stress to use ready-made chains to maintain homeostasis. In pilot examinations we found that free ubiquitin chains suppress toxicity from disease-causing proteins. Our pilot data lead us to hypothesize that unanchored poly-ubiquitin is beneficial to the cellular response to misfolded disease proteins. We propose to test this hypothesis through three aims that utilize a combination of physiological and biochemical assays.

与年龄相关的神经系统疾病是多种多样的，并将继续增长的重要性