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

蛋白质错误折叠是衰弱的年龄相关疾病，如ALS，阿尔茨海默氏症， 帕金森氏症和亨廷顿氏症在我们今天的社会中正在增加。激活热休克 转录因子，HSF1，一种在所有生命王国中保守的转录因子，负责 分子伴侣和其他有利于生存的基因产物的表达，导致显著改善 蛋白质病动物模型中蛋白质聚集的毒性效应。HSF1的激活时间较长 据了解，这是一种细胞的自主反应，由错误折叠蛋白质种类的增加引发。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，细胞积累错误折叠 但不能激活HSF1，从而有效地对抗蛋白质聚集和毒性。因此， 了解如何在原位激活HSF1可以提供一种强有力的干预手段 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，作用于 通过G蛋白偶联的5-HT4受体(5-HT4R)，可以激活HSF1，增加分子伴侣 表情。我们的初步数据进一步表明，5-羟色胺能信号足以减少细胞内 哺乳动物细胞培养模型中多聚Q扩张蛋白的蛋白质包涵体。基于这些令人兴奋的 研究中，我们建议检验通过5-HT4R调节5-羟色胺能信号可以保护 通过激活HSF1来对抗亨廷顿病小鼠模型中的蛋白病变，并打算解剖 这种保护的细胞内机制。如果成功，我们的研究将为 探讨5-HT4R激动剂在防治破坏性神经退行性疾病中的作用 并提供证据表明，动机状态中5-羟色胺依赖的变化可以调节 蛋白质病。

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.