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

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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.