The widespread abnormal aggregation of proteins in neurodegenerative diseases has been postulated to arise as a symptom of deficiencies in the quality control networks that govern proteostasis (protein-folding homeostasis). These protein quality control networks comprise of over 800 known proteins in humans, yet it remains unclear which aspects of this network become defective in disease. We previously reported that soluble misfolded protein Huntingtin exon 1 was acutely toxic to cells before it aggregated [1], which led us to postulate the existence of a feedback mechanism that involves the targeting of soluble misfolded protein for clearance, which if overwhelmed, triggers apoptosis. To test this hypothesis and to explore more broadly the elements of the quality control network that are relevant to disease mechanisms, we are implementing a genome-wide CRISPR/dCas9 based SAM (Synergistic Activation Mediator) screen. Our approach is multipronged. The first part involves screening for genes that modify the toxicity of a “designer” misfolded protein we made that is toxic to cell culture. We anticipate the genes yielded by this screen to include candidates that operate a general feedback response to misfolded proteins. The second approach involves screens targeting proteostasis imbalance more broadly using novel reporters we have developed for chaperone activity and the accumulation of unfolded and aggregated protein [2, 3].