Enhancement of Protein Breakdown through PKG-mediated Phosphorylation of the Proteasome

通过 PKG 介导的蛋白酶体磷酸化增强蛋白质分解

基本信息

批准号：
9792258
负责人：
Jordan VerPlank
金额：
$ 6.16万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9792258
关键词：
26S proteasome Adenylate Cyclase Affect Aftercare Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Autophagocytosis Biochemical Brain Catalytic Domain Cell Aggregation Cells Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic GMP-Dependent Protein Kinases Disease Disease Progression Exhibits FDA approved Failure Frontotemporal Dementia Goals Heart Human Impairment Investigation Lysosomes Mammalian Cell Mass Spectrum Analysis Mediating Methods Modeling Modification Mus Neurodegenerative Disorders Parkinson Disease Peptide Hydrolases Pharmacology Phosphodiesterase Inhibitors Phosphorylation Phosphotransferases Physiologic pulse Physiological Proteins Site-Directed Mutagenesis Soluble Guanylate Cyclase System Tauopathies Testing Therapeutic Tissues Ubiquitin Ubiquitination Zebrafish base cell type combat frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic regulatory protein inhibitor/antagonist misfolded protein multicatalytic endopeptidase complex mutant neuroblastoma cell novel strategies overexpression phosphodiesterase IV prevent protein B protein degradation proteostasis proteotoxicity sildenafil superoxide dismutase 1 tau mutation

项目摘要

Project Summary / Abstract The ubiquitin proteasome system (UPS) degrades the majority of proteins in mammalian cells and one of its primary functions is to selectively eliminate misfolded, potentially toxic proteins. In the UPS, protein substrates are modified by the attachment of chains of ubiquitin molecules, which target the protein for rapid degradation by the 26S proteasome. It is generally assumed that ubiquitination determines the rate of protein degradation by the UPS, but recent studies have shown that the activity of 26S proteasomes is tightly regulated and can determine rates of protein degradation in cells. Our lab and collaborators recently found that agents that raise cAMP cause the Protein Kinase A-mediated phosphorylation of the 26S subunit Rpn6 and the enhancement of multiple proteasome activities. This modification increases the capacity in cells and mouse brains to degrade misfolded, aggregation-prone proteins (e.g. mutant Tau and SOD1) that cause neurodegenerative diseases. Thus, pharmacological enhancement of proteasome function is an exciting new approach to combat various aging-associated diseases. I recently found that treatments that raise cGMP and activate Protein Kinase G also stimulate proteasome activity and protein degradation in cells. This cGMP-mediated stimulation was not due to Rpn6 phosphorylation, and therefore occurs by a different mechanism than raising cAMP. I am proposing an in-depth investigation to determine 1.) how raising cGMP stimulates proteasome function, 2.) the effect of raising cGMP on the degradation of different types of cell proteins and 3.) whether FDA-approved pharmacological agents that increase cGMP levels (e.g. PDE5 inhibitors) enhance the clearance of mutant proteins that cause Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Parkinson’s Disease. These studies should clarify the mechanisms and importance of this new mode of regulating protein degradation and its therapeutic potential.

项目摘要 /摘要泛素蛋白酶体系统（UPS）哺乳动物细胞中的大多数蛋白质和一个 OFS主要功能是在UPS中选择性地消除错误折叠的潜在有毒蛋白。底物是通过泛素分子链的附着来改变底物的，泛素分子的链条靶向蛋白质以快速 26S蛋白酶的降解。 UPS的降解，但最近的研究表明，将26S蛋白酶体的活性紧密定期，可以确定细胞中蛋白质降解的速率。引起蛋白激酶A介导的26S亚基RPN6和TEE的蛋白激酶A介导的磷酸化的药物增强多种蛋白酶体活动。大脑会降解错误折叠的，容易发生的蛋白质（例如突变的tau和sod1）神经退行性疾病。打击各种相关疾病的方法。最近，我发现了引起CGMP并激活蛋白激酶G的治疗方法也刺激细胞中的蛋白酶体活性和蛋白质降解。我建议深入。调查确定1.）提高CGMP如何刺激蛋白酶体功能，2。）上升CGMP的效果关于不同类型的细胞蛋白的降解3。）这会增加CGMP水平（例如PDE5脱离病人）增强了引起突变蛋白的清除率阿尔茨海默氏病，肌萎缩性侧索硬化症，额颞痴呆和帕金森氏病。研究应阐明这种调节蛋白质的新模式的机制和重要性退化及其治疗潜力。