Stress Regulation of Synaptic Transmission

突触传递的压力调节

• 批准号: 8500483
• 负责人: DEREK SIEBURTH
• 金额: $ 33.51万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500483
• 关键词: Alzheimer' s Disease; Biological Models; Caenorhabditis elegans; Candidate Disease Gene; Cell Nucleus; Cell physiology; Cellular Stress; Cholinergic Receptors; Family; Functional disorder; Genes; Goals; Health; Impaired cognition; Lead; Learning; Mediating; Metabolic; Molecular; Motivation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Neurotransmitters; Onset of illness; Orthologous Gene; Oxidative Stress; Parkinson Disease; Pathway interactions; Play; Presynaptic Terminals; Proteins; Regulation; Regulatory Pathway; Role; Series; Signal Pathway; Signal Transduction; Stress; Synapses; Synaptic Transmission; Testing; Toxin; Vertebrates; Work; biological adaptation to stress; body system; brain cell; functional genomics; insight; neuronal excitability; neuronal survival; neurotransmission; normal aging; novel; nrf1 protein; presynaptic; prevent; programs; research study; response; synaptic function; transcription factor

DESCRIPTION (provided by applicant): The long-term goal of this project is to determine mechanisms by which synaptic transmission is regulated by cellular stress pathways. The motivation of this project is twofold. First, stress plays a critical role in cognitive dysfunction and neurodegeneration associated with neurodegenerative diseases. Second, although much has been learned about how cellular responses to stress can promote neuronal survival, far less is known about how these responses can regulate neuronal function. We propose to characterize the role of a stress response pathway that mediates cellular responses to oxidative stress in regulating synaptic function using C. elegans as a model system. We previously identified a new protein that is conserved in vertebrates, WDR-23, in a functional genomic screen for genes required for synaptic transmission at the neuromuscular junction. We found that WDR-23 promotes the secretion of neurotransmitter from presynaptic terminals by antagonizing the activity of the transcription factor SKN-1. SKN-1 is the ortholog of the mammalian NF-E2 related factor (Nrf) family of transcription factors, which are critical for protecting neurons form the neurodegenerative effects of oxidative stress. We found that skn-1 activity is required for proper neurotransmission and for expression of a neuron-specific gene, acr-2, which encodes an acetylcholine receptor subunit of unknown function. Here we propose to test the hypothesis that SKN-1 regulates synaptic transmission in response to stress. First, we will determine how SKN-1 activity is negatively regulated by WDR-23 and by stress pathways in neurons. Second, we will identify the environmental and cellular stress pathways that activate SKN-1 in neurons. Third, we will determine how SKN-1-activated transcriptional programs generate changes in neurotransmitter secretion and synaptic function. These experiments will provide insights into the molecular mechanisms by which the SKN-1/Nrf stress response pathway regulates synaptic function. In summary, this work will establish a novel role for SKN-1/Nrf-mediated transcriptional programs in regulating synaptic transmission, and should provide insights into how stress impacts synaptic dysfunction associated with neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Many neurodegenerative disorders, such as Alzheimer's and Parkinson's disease are thought to be caused by toxins that accumulate in brain cells as the result of normal ageing. Here we propose to study how a natural system that the body uses to remove these toxins can impact normal brain cell function, and how it can be used to delay or prevent the onset of these diseases.

描述（由申请人提供）：该项目的长期目标是确定细胞应激途径调节突触传递的机制。这个项目的动机是双重的。首先，压力在与神经退行性疾病相关的认知功能障碍和神经退行性疾病中起着关键作用。其次，尽管我们对细胞对压力的反应如何促进神经元存活已经了解了很多，但对这些反应如何调节神经元功能的了解却少得多。我们建议以秀丽隐杆线虫为模型系统，描述应激反应途径在调节突触功能中的作用，该途径介导细胞对氧化应激的反应。我们之前在神经肌肉连接处突触传递所需基因的功能基因组筛选中发现了一种在脊椎动物中保守的新蛋白WDR-23。我们发现WDR-23通过拮抗转录因子SKN-1的活性，促进突触前末端神经递质的分泌。SKN-1是哺乳动物NF-E2相关因子（Nrf）转录因子家族的同源物，这对于保护神经元免受氧化应激的神经退行性影响至关重要。我们发现，正常的神经传递和神经元特异性基因acr-2的表达需要skn-1活性，该基因编码功能未知的乙酰胆碱受体亚基。在这里，我们提出验证SKN-1在应激反应中调节突触传递的假设。首先，我们将确定SKN-1活性如何受到WDR-23和神经元应激途径的负调控。其次，我们将确定激活神经元中SKN-1的环境和细胞应激途径。第三，我们将确定skn -1激活的转录程序如何产生神经递质分泌和突触功能的变化。这些实验将深入了解SKN-1/Nrf应激反应通路调节突触功能的分子机制。总之，这项工作将确立SKN-1/ nrf介导的转录程序在调节突触传递中的新作用，并为应激如何影响与神经退行性疾病相关的突触功能障碍提供见解。