Uncovering how serotonergic signaling non-autonomously regulates protein homeostasis

 描述（由申请人提供）：“蛋白质病”，即蛋白质错误折叠和聚集的疾病，是使人衰弱的年龄相关疾病，例如ALS、阿尔茨海默氏病、帕金森氏病和亨廷顿氏病，对于这些疾病，目前没有减少细胞功能障碍和死亡的干预措施。利用细胞自身对蛋白质错误折叠的保护性反应，如热休克反应（HSR），可显著改善所有蛋白质病动物模型中蛋白质聚集的毒性作用。最近的研究表明，生物体单个细胞的HSR处于神经系统的非自主控制之下。这个提议的目的是精确地确定神经元如何控制另一个细胞中的HSR。我们已经确定了这种细胞保护机制的一个关键因素：热敏诱导的5-羟色胺（5-HT）释放是必要的，足以诱导其他细胞中的HSR，从而抑制蛋白质聚集和错误折叠。我们通过HSF-1（负责保护性热休克蛋白（HSP）基因表达的转录因子）的实时成像，结合完整动物中特定神经元的光遗传学激发，证明了这一点。使用我们实验室开发的技术，我们将研究组织间的信号传导机制，通过该机制，感觉压力感知导致细胞保护。所提出的工作的创新之处在于，它将阐明，深入，第一次，细胞非自主控制的HSR的机制。衰老导致有机体承受压力的能力不可避免地下降。目前还不清楚是否在压力信号传导机制本身的效率下降，有助于这种老化依赖性损伤的压力反应。我们在解剖神经感觉系统向远端组织发出压力信号并非自主控制其反应的机制方面的专业知识使我们有机会解决这个问题。假设：温度感应诱导的5-HT释放激活保护蛋白质稳态的适应性细胞应激反应。目标1.温度感觉神经元如何引起5-HT从多巴胺能神经元的释放？目标2. 5-HT在反应细胞中激活了哪些组织间应激信号通路？

 DESCRIPTION (provided by applicant):"Proteinopathies," diseases of protein misfolding and aggregation, are debilitating age-related diseases such as ALS, Alzheimer's, Parkinson's and Huntington's Diseases, for which there are currently no interventions to reduce cell dysfunction and death. Harnessing the cell's own protective responses to protein misfolding such as the heat shock response (HSR) dramatically ameliorates the toxic effects of protein aggregation in all animal models of proteinopathies. Recent studies have shown that the HSR of individual cells of an organism is under non-autonomous control of the nervous system. The objective of this proposal is to determine precisely how neurons control the HSR in another cell. We have identified a crucial element of this cytoprotective mechanism: thermosensory-induced serotonin (5-hydroxytryptamine, 5-HT) release is necessary and sufficient to induce the HSR in other cells and thereby suppress protein aggregation and misfolding. We show this by live imaging of HSF-1, the transcription factor responsible for the expression of protective heat shock protein (HSP) genes, in combination with optogenetic excitation of specific neurons in intact animals. Using techniques developed in our laboratory, we will investigate the inter-tissue signaling mechanisms by which sensory stress perception results in cytoprotection. The innovation of the proposed work is that it will elucidate, in-depth, for the first time, a mechanism of cell non-autonomous control of the HSR. Aging results in the inevitable decline in an organism's ability to withstand stress. It is unclear whether decreases in the efficiency of stress signaling mechanisms themselves contribute to this aging-dependent impairment of stress responses. Our expertise in dissecting the mechanisms by which the neurosensory system signals stress to distal tissues, and non-autonomously controls their response allows us a unique opportunity to address this question. Hypothesis: Thermosensory-induced release of 5-HT activates adaptive cellular stress responses that protect protein homeostasis. Aim 1. How do thermosensory (AFD) neurons elicit 5-HT release from serotonergic neurons? Aim 2. What inter-tissue stress signaling pathways are activated by 5-HT in responsive cells?