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Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies., Competing Interests: Declaration of interests H.Y.Z. is a member of the Board of Regeneron, is the co-founder of Cajal Neuroscience, and is on the Scientific Advisory Board of The Column Group, but none of the work in the paper has any relevance to the research at Regeneron. H.Y.Z. is a member of the Neuron Advisory Board., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)