Discovery of druggable pathways that prevent cell death caused by proteotoxic stress



 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative disorder (ND) that afflicts more than 6 million people worldwide. This number will continue to rise in the coming years as the average age of our society increases. While several risk genes are known to predispose to PD, we still incompletely understand this complex disease and, as a consequence, there are no therapies that slow the progression of this debilitating and ultimately fatal disease. To address this issue, many research groups have searched for new therapeutic targets using simple organisms to model PD pathogenesis. Our lab has previously used the yeast Saccharomyces cerevisiae to pinpoint the cellular functions that mediate the toxicity of the misfolded proteins that cause neurodegenerative disorders, including PD (α-syn), Alzheimer's (Aβ), Huntington's (polyQ), and ALS (TDP-43). Genetic screens against this yeast α-syn model have identified suppressors of toxicity that are also protective in neurons. A previous screen of genetically encoded cyclic peptides revealed the presence of a druggable target that protects both yeast and C. elegans neurons from α-syn toxicity, but the mechanism of action of these compounds remains unknown. Aim 1 of the current proposal seeks to identify the mechanistic target(s) of these bioactive cyclic peptides using modern chemical biology approaches, including photocrosslinking and cellular thermal shift assays. In Aim 2, I propose to leverage the genetic tractability of yeast to determine which cellular pathways are necessary and/or sufficient for the protective effect of the cyclic peptides. Finally, in Aim 3 I will leverage recent advances in the technology for screening large libraries o genetically encoded cyclic peptides to develop more efficacious analogs as candidate therapeutics for the treatment of PD and other synucleinopathies. Overall, these studies aim to unveil a new candidate therapeutic target for PD, establish its cellular context, and develop next-generation cyclic peptides that may form the basis of a new class of disease-modifying drugs for PD.