Stress Regulation of Synaptic Transmission

描述（由申请人提供）：本项目的长期目标是确定突触传递受细胞应激途径调节的机制。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。第二，尽管人们已经了解了很多关于细胞对压力的反应如何促进神经元存活的知识，但对这些反应如何调节神经元功能的了解却少得多。我们建议使用C. elegans作为一个模型系统。我们以前确定了一个新的蛋白质，是保守的脊椎动物，WDR-23，在功能基因组筛选所需的基因在神经肌肉接头的突触传递。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梢神经递质的分泌。SKN-1是哺乳动物NF-E2相关因子（Nrf）家族转录因子的直系同源物，其对于保护神经元免受氧化应激的神经退行性作用至关重要。我们发现skn-1的活性是正常神经传递和神经元特异性基因acr-2表达所必需的，acr-2编码一种功能未知的乙酰胆碱受体亚基。在这里，我们建议测试的假设，SKN-1调节突触传递响应压力。 首先，我们将确定SKN-1活性如何受到WDR-23和神经元中应激通路的负调节。 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。这些实验将提供深入了解SKN-1/Nrf应激反应途径调节突触功能的分子机制。 总之，这项工作将建立一个新的作用SKN-1/NRF介导的转录程序在调节突触传递，并应提供深入了解如何应力影响与神经退行性疾病相关的突触功能障碍。 公共卫生相关性：许多神经退行性疾病，如阿尔茨海默氏症和帕金森氏症，被认为是由正常衰老导致的脑细胞中积累的毒素引起的。在这里，我们建议研究身体用于清除这些毒素的自然系统如何影响正常的脑细胞功能，以及如何使用它来延迟或预防这些疾病的发作。

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.