Uncovering how serotonergic signaling non-autonomously regulates protein homeostasis

 描述(申请人提供)：蛋白质病，蛋白质错误折叠和聚集的疾病，是与年龄相关的衰弱疾病，如肌萎缩侧索硬化症、阿尔茨海默氏症、帕金森病和亨廷顿病，目前还没有针对这些疾病的干预措施来减少细胞功能障碍和死亡。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)，可以显着改善所有蛋白质病动物模型中蛋白质聚集的毒性效应。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。这项提议的目的是准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元素：热感觉诱导的5-羟色胺(5-羟色胺，5-HT)释放是诱导其他细胞HSR的必要条件和充分条件，从而抑制蛋白质聚集和错误折叠。我们通过对HSF-1的实时成像来证明这一点，HSF-1是负责保护性热休克蛋白(HSP)基因表达的转录因子，与完整动物中特定神经元的光遗传兴奋相结合。利用我们实验室开发的技术，我们将研究组织间信号传递机制，通过这些机制，感觉应激感知导致细胞保护。这项拟议工作的创新之处在于，它将首次深入阐明细胞对高铁的非自主控制机制。衰老会不可避免地导致生物体承受压力的能力下降。目前尚不清楚应激信号机制本身的效率降低是否会导致这种依赖于年龄的应激反应损伤。我们在剖析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，使我们有一个独特的机会来解决这个问题。假设：热感觉诱导的5-羟色胺的释放激活了适应性细胞应激反应，保护了蛋白质的动态平衡。目的1.热感觉(AFD)神经元如何诱导5-羟色胺能神经元释放5-羟色胺？目的2.在反应细胞中，5-羟色胺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?