Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress-Responsive Activation of PERK Signaling.
Angew Chem Int Ed Engl
; 60(4): 1831-1838, 2021 01 25.
Article
em En
| MEDLINE
| ID: mdl-33210431
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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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas tau
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Fármacos Neuroprotetores
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EIF-2 Quinase
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Descoberta de Drogas
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Proteostase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2021
Tipo de documento:
Article