Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress-Responsive Activation of PERK Signaling
- Authors
- Shin, Young-Hee; Cho, Hana; Choi, Bo Young; Kim, Jonghoon; Ha, Jaeyoung; Suh, Sang Won; Park, Seung Bum
- Issue Date
- Jan-2021
- Publisher
- WILEY-V C H VERLAG GMBH
- Keywords
- ER stress response; PERK signaling; proteostasis; target Identification; tauopathies
- Citation
- ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, v.60, no.4, pp.1831 - 1838
- Journal Title
- ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
- Volume
- 60
- Number
- 4
- Start Page
- 1831
- End Page
- 1838
- URI
- http://scholarworks.bwise.kr/ssu/handle/2018.sw.ssu/40087
- DOI
- 10.1002/anie.202013915
- ISSN
- 1433-7851
- 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.
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Collections - College of Natural Sciences > Department of Chemistry > 1. Journal Articles
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