Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD

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Project Summary Neurodegeneration is an increasing public health challenge and remains an unsolved biomedical problem. Protein misfolding and aggregation are a central feature of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The complexity of neurodegeneration calls for large-scale unbiased screening studies. Over the past few years, we have made breakthrough observations with significant implications for understanding the cellular defense systems against proteotoxicity underlying pathogenesis in ALS/FTD. Using a unique blend of genetic, biochemical, and cell biological approaches, we have uncovered novel pathways that enable reprogramming of protein quality control to counter proteotoxicity. The newly proposed work in this project is aimed at elucidating mechanisms underlying newly identified regulators and master switches in protein quality control. The studies on the previously unrecognized higher-order regulators could expand our understanding of proteotoxic-stress-responsive quality control systems in the cell, beyond the well-established heat shock response or unfolded protein response. Our unique abilities to contribute to this field are at both conceptual and technical levels: In additional to novel pathways, we have developed unique C. elegans/mammalian reporter systems to study proteotoxicity-associated neurodegeneration, and our recent success bodes well for future plans. Furthermore, our expanding repertoire of tools will allow us to extend the findings to diverse models and patient cells. The specific aims are to elucidate the mechanisms through which a novel conserved pathway, involving a previously unknown transcriptional master switch, in the regulation of protein quality control, to delineate the pathways through which a novel target and its signaling pathway regulate proteotoxicity, and to develop new tools for more advanced search for key regulators of proteotoxicity and quality control. The findings will not only provide novel entry points for understanding the toxicities of key ALS/FTD proteins, such as SOD1, TDP-43, and C9orf72 DPRs, but also reveal molecular targets for harnessing the cellular defense system to prevent and treat the relevant neurodegenerative diseases. We predict that the advances gained through our research efforts will eventually lead to new therapeutic interventions to address these diseases in the world’s rapidly aging population.