The EIF2α-PERK Signaling Pathway Mediates Manganese Exposure-Induced A1-Type Astrocytes Activation via Endoplasmic Reticulum Stress

Elevated exposure to manganese (Mn) has been linked to a broad spectrum of neurological disorders, including motor dysfunction. Neuroinflammation with excessively activated astrocytes plays a critical role in the pathogenesis and progression of neurodegenerative diseases. Astrocyte-mediated neuroinflammation plays a dual role due to distinct astrocyte phenotypes, including deleterious A1 and neuroprotective A2. Our previous studies have confirmed that Mn induces activation of astrocytes in the central nervous system, and endoplasmic reticulum (ER) stress has been verified to regulate A1 activation; however, the molecular mechanisms underlying Mn-induced neurotoxicity remain incompletely understood. We establish in vivo and in vitro Mn exposure models and observed that Mn induced A1 activation of astrocytes in both models, with upregulation of A1-specific markers. Sub-cellular morphological analysis showed Mn-induced ER stress in A1-type astrocytes. We found that EIF2α-PERK signaling pathways are activated in astrocytes and drive ER stress and mitochondrial impairment. Suppression of astrocytic PERK, using either ISRIB or GSK2606414, alleviates Mn-induced ER stress and A1 activation, which in turn mitigates the motor deficits induced by Mn exposure. These findings reveal that inhibition of PERK can ameliorate Mn-induced neurotoxicity by suppressing astrocyte activation and preserving organelle homeostasis, offering a potential therapeutic strategy to mitigate the harmful effects of Mn toxicity.