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The development of tau\u2010targeting therapies is therefore extremely important but efficient strategies or protein targets are still unclear. Here, we performed a cell\u2010based phenotypic screening under endoplasmic reticulum (ER) stress conditions and identified a small molecule, SB1617, capable of suppressing abnormal tau protein aggregation. By applying label\u2010free target identification technology, we revealed that the transient enhancement of protein kinase\u2010like endoplasmic reticulum kinase (PERK) signaling pathway through the inhibition of stress\u2010responsive SB1617 targets, PDIA3 and DNAJC3, is an effective strategy for regulating proteostasis in tauopathies. The molecular mechanism and the promising efficacy of SB1617 were demonstrated in neuronal cells and a mouse model with traumatic brain injury, a tauopathy known to involve ER stress.<\/jats:p>","DOI":"10.1002\/anie.202013915","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T03:12:30Z","timestamp":1605755550000},"page":"1831-1838","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress\u2010Responsive Activation of PERK Signaling"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0235-7081","authenticated-orcid":false,"given":"Young\u2010Hee","family":"Shin","sequence":"first","affiliation":[{"name":"CRI Center for Chemical Proteomics Department of Chemistry Seoul National University  Seoul 08826 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