Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2

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.