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 mediated through activation of the NRF2-regulated oxidative stress response. We demonstrate that AA147 activates NRF2 selectively in neuronal-derived cells through a mechanism involving metabolic activation to a reactive electrophile and covalent modification of KEAP1—a mechanism analogous to that involved in the AA147-dependent activation of ATF6. These results define the potential for AA147 to protect against glutamate-induced oxidative toxicity and highlight the potential for metabolically activated proteostasis regulators like AA147 to activate both protective ATF6 and NRF2 stress-responsive signaling pathways to mitigate oxidative damage associated with diverse neurologic diseases.

Ameliorative Effects of Peptide Phe-Leu-Ala-Pro on Acute Liver and Kidney Injury Caused by CCl4 via Attenuation of Oxidative Stress and Inflammation

“…In the present study, the collagen peptide FLAP increased the activity of SOD, GSH-Px, and CAT in the liver and kidneys of mice, indicating that FLAP reduced oxidative damage in vivo by scavenging more free radicals. The Nrf2/ARE pathway is an important defense response system to oxidative stress. , Nrf2 can regulate the expression levels of antioxidant genes such as SOD, GSH-Px, and HO-1. This study showed that FLAP treatment significantly up-regulated the expression of Nrf2 in both the liver and kidneys, thereby increasing HO-1 levels by more than three times relative to the CCl 4 group.…”

Role of Nrf2 in Parkinson’s Disease: Toward New Perspectives

“…Meanwhile, genes, such as ATF6 and the inositol-requiring enzyme 1 (IRE1)/X-box protein 1 (XBP1s), were activated via DESeq2 analysis of genes. Together, activation of Nrf2 in neurons by small protein homeostasis regulators involves selection of mechanisms for electrophilic and covalent modification of Keap1 (Rosarda et al, 2021).…”

Protein quality control of N-methyl-D-aspartate receptors

“…For example, the small molecule AA147 is a proteostasis regulator that activates the 10.3389/fncel.2022.907560 ATF6 arm of the UPR, thereby reducing ER stress. In addition to this mechanism of action, AA147 also protects against glutamate-mediated excitotoxcity by activating nuclear factor erythroid 2-related factor 2 (NRF2) regulated oxidative stress response, and thus reduces oxidative damage to cells (Rosarda et al, 2021). While there is currently no direct evidence that NMDAR signaling results in the oxidative stress that this drug is capable of reducing, it raises an additional consideration for dual effects of future therapeutics.…”