Role of serotonergic-activation of heat shock transcription factor in the regulation of age-related protein misfolding and toxicity in mammalian systems

热休克转录因子的血清素激活在哺乳动物系统中年龄相关蛋白错误折叠和毒性调节中的作用

• 批准号: 10478973
• 负责人: Rocio Gomez-Pastor
• 金额: $ 11.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478973
• 关键词: Address; Affect; Aging; Agonist; Alzheimer' s Disease; Animal Model; Behavioral; Biochemical; Biological Assay; Brain; Caenorhabditis elegans; Cell Culture System; Cell Culture Techniques; Cell Line; Cell model; Cells; Cellular biology; Corpus striatum structure; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Dependovirus; Disease; Doxycycline; Ensure; Experimental Designs; Extracellular Signal Regulated Kinases; GTP-Binding Proteins; Gastrointestinal Diseases; Gene Expression; Genes; Glutamine; Goals; Heat shock factor; Human; Huntington Disease; In Situ; Intervention; Intraperitoneal Injections; Life; Mammalian Cell; Measures; Mediating; Mental Depression; Metabolism; Modeling; Molecular Chaperones; Motivation; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuromodulator; Neurons; Parkinson Disease; Pathology; Patients; Peripheral Nervous System; Pharmacology; Phosphorylation; Physiological; Physiological Processes; Proteins; Publishing; Regulation; Role; Serotonin; Serotonin Agonists; Serotonin Receptors 5-HT4; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Societies; Stress; Symptoms; Synapses; System; Techniques; Testing; Time; Tissues; Toxic effect; Work; age related; age related neurodegeneration; base; cohort; density; experimental study; familial amyotrophic lateral sclerosis; gene product; heat shock transcription factor; in vitro Model; in vivo; misfolded protein; motor behavior; mouse model; mutant; nerve stem cell; neuropsychiatric disorder; polyglutamine; programs; protein aggregation; protein folding; protein misfolding; proteostasis; response; superoxide dismutase 1; transcription factor; transcriptome sequencing; translational impact

Protein misfolding is central to the pathology of the debilitating age-related diseases such as ALS, Alzheimer's, Parkinson's and Huntington's diseases that are increasing in our society today. Activating the heat shock transcription factor, HSF1, a transcription factor conserved across all kingdoms of life and responsible for the expression of molecular chaperones and other pro-survival gene products, results in a dramatic amelioration of the toxic effects of protein aggregation in animal models of proteinopathies. The activation of HSF1 was long understood to be an autonomous response of cells triggered by the increase in misfolded protein species. Yet, in tissues of patients suffering from the age-related neurodegenerative diseases, cells accumulate misfolded proteins but do not activate HSF1 to effectively counteract protein aggregation and toxicity. Thus, understanding how to activate HSF1 in situ could provide a powerful means to intervene in proteinopathies. Our recent studies have demonstrated that increases in the neuromodulator serotonin, acting through the G-protein coupled 5-HT4 receptor (5-HT4R), can activate HSF1 and increase molecular chaperone expression. Our preliminary data further show that serotonergic signaling is sufficient to decrease intracellular protein inclusions of polyQ expansion proteins in cultured mammalian cell models. Based on these exciting studies, we propose to test the hypothesis that modulating serotonergic signaling through 5-HT4R can protect against proteinopathies in a mouse model of Huntington's Disease by activating HSF1, and intend to dissect the intracellular mechanisms underlying such protection. If successful, our studies will establish a rational basis for exploring the role for 5-HT4R agonists in the protection against devastating neurodegenerative diseases of aging and provide evidence that serotonin-dependent changes in motivational state can modulate proteinopathies.

蛋白质错误折叠对于衰弱的年龄相关疾病的病理至关重要，例如ALS，阿尔茨海默氏症， 帕金森氏症和亨廷顿的疾病在当今社会中正在增加。激活热冲击 转录因子HSF1，一种在生活的所有王国中保留的转录因子，并负责 分子伴侣和其他促生存基因产物的表达，导致急剧改善 蛋白质聚集在蛋白质病模型中的毒性作用。 HSF1的激活很长 理解是由错误折叠蛋白质物种增加引发的细胞的自主反应。然而， 在患有与年龄相关的神经退行性疾病的患者的组织中，细胞积累了错误折叠的 蛋白质，但不会激活HSF1有效抵消蛋白质聚集和毒性。因此， 了解如何在原位激活HSF1可以提供一种有力的方法来干预 蛋白质病。我们最近的研究表明，神经调节剂5-羟色胺的增加，作用 通过G蛋白耦合5-HT4受体（5-HT4R），可以激活HSF1并增加分子伴侣 表达。我们的初步数据进一步表明，血清素能信号足以减少细胞内 培养的哺乳动物细胞模型中PolyQ膨胀蛋白的蛋白质包含。基于这些令人兴奋的 研究，我们建议测试以下假设，即通过5-HT4R调节5-羟色胺能信号传导可以保护 通过激活HSF1来反对亨廷顿氏病小鼠模型中的蛋白质病，并打算剖析 细胞内机制进行了这种保护。如果成功，我们的研究将建立合理的基础 探索5-HT4R激动剂在防止衰老的毁灭性神经退行性疾病中的作用 并提供证据表明5-羟色胺依赖于动机状态的变化可以调节 蛋白质病。