This project addresses an unmet medical need- the lack of effective treatment for any of the aging-associated neurodegenerative diseases. Due to the worldwide aging of the population, by 2050 it is expected that over 135 million people will suffer from these devastating disorders. They display complex and partly distinctive pathophysiological profiles, yet they all share a prime feature: accumulation of aberrantly processed and misfolded proteins into aggregates. Therefore, they are often called neuronal proteinopathies (NPs).
Based on an unbiased screen, we found that activation of serotonergic signaling suppressed protein aggregation and restored motor behavior in animal models of polyglutamine diseases, establishing a mechanistic link between suppression of disease-protein toxicity and aggregation (proteotoxicity) and the neurotransmitter serotonin (5-HT). 5-HT signaling pathways integrate basic physiology and essential brain functions, suggesting an important and overarching mode-of-action for this neurotransmitter in the brain. This project aims at understanding how activation of 5-HT neurotransmission modulates protein homeostasis (aka. proteostasis) in the brain, potentially impacting in nearly all processes that depend on protein folding and function in cells. Using a multi-disciplinary approach, combining whole-organism fast-throughput drug screening, in vivo folding sensors, targeted genome editing, opto/chemogenetic manipulation of neuronal activity and multi-omics analyses, we propose to accelerate drug discovery by identifying, among the 5-HT system-targeting drugs (mostly already in use in the clinics), an enhancer of proteostasis and to uncover the cellular-pathways that regulate proteotoxicity. By challenging the traditional approach for drug discovery and development, this project has the potential to define 5-HT as a biological suppressor of toxic protein aggregation and to identify biomarkers of 5-HT-mediated therapeutics for prospective clinical studies in NP patients.