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Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress‐Responsive Activation of PERK Signaling
Author(s) -
Shin YoungHee,
Cho Hana,
Choi Bo Young,
Kim Jonghoon,
Ha Jaeyoung,
Suh Sang Won,
Park Seung Bum
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202013915
Subject(s) - proteostasis , endoplasmic reticulum , unfolded protein response , tauopathy , neuroprotection , microbiology and biotechnology , neuroscience , biology , phenotype , kinase , tau protein , protein kinase a , neurodegeneration , alzheimer's disease , disease , medicine , biochemistry , gene
Abstract Tau protein aggregates are a recognized neuropathological feature in Alzheimer's disease as well as many other neurodegenerative disorders, known as tauopathies. The development of tau‐targeting therapies is therefore extremely important but efficient strategies or protein targets are still unclear. Here, we performed a cell‐based phenotypic screening under endoplasmic reticulum (ER) stress conditions and identified a small molecule, SB1617, capable of suppressing abnormal tau protein aggregation. By applying label‐free target identification technology, we revealed that the transient enhancement of protein kinase‐like endoplasmic reticulum kinase (PERK) signaling pathway through the inhibition of stress‐responsive 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.