Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2.

ABSTRACT: The extracellular accumulation of glutamate is a pathologic hallmark of numerous neurodegenerative diseases including ischemic stroke and Alzheimer's disease. At high extracellular concentrations, glutamate causes neuronal damage by promoting oxidative stress, which can lead to cellular death. This has led to significant interest in developing pharmacologic approaches to mitigate the oxidative toxicity caused by high levels of glutamate. Here, we show that the small molecule proteostasis regulator AA147 protects against glutamate-induced cell death in a neuronal-derived cell culture model. While originally developed as an activator of the activating transcription factor 6 (ATF6) arm of the unfolded protein response, this AA147-dependent protection against glutamate toxicity is primarily me

SUBMITTER: Rosarda JD 

PROVIDER: S-EPMC8689639 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature