Project Summary Protein quality control is a fundamental system in the cell that is important for normal cellular functions and defense against potential pathogenic insults. Protein misfolding and aggregation are a central feature of many neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). The complexity of neurodegeneration calls for large-scale unbiased screening studies. Over the past few years, we have made breakthrough observations that have significant implications for the understanding of cellular defense systems against proteotoxicity. Using a unique blend of biochemical, genetic, and cell biological approaches, we discovered a novel pathway to reprogram protein quality control, and with new genetic hits related to this pathway. Our work has elucidated a previously unrecognized network in protein quality control. The studies on this network 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. The findings will suggest new strategies for harnessing the cellular defense system to prevent and treat the relevant forms of neurodegenerative diseases associated with proteotoxicity. Our project will be focused on investigating novel molecular targets that are identified through unbiased screens and testing new small molecule compounds that have been designed to be specific inhibitors of this target. We predict that the advances gained through our research efforts will eventually lead to new therapeutic interventions to address the relevant neurodegenerative diseases.