Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress‐Responsive Activation of PERK Signaling

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.
A novel neuroprotective compound, SB1617, was developed via phenotypic assay by image‐based monitoring of tau protein aggregation. Label‐free target identification study revealed that SB1617 inhibits PDIA3 and DNAJC3, thereby regulates tau proteostasis through the activation of PERK signaling pathway in a stress‐responsive manner. The administration of SB1617 showed neuroprotective effects in mice with tauopathy involving ER stress.