Manganese (Mn), the fifth most abundant metal in Earth's crust, is extensively mined for industrial, energy, and agricultural applications, resulting in excess human exposure. Mn accumulates in the central nervous system (CNS) and triggers neurotoxicity; emerging evidence indicates that activation of the A1 astrocyte phenotype is an early and critical event in this process. However, the upstream molecular cues that drive A1 conversion remain incompletely understood. Here we combined in vivo (C57BL/6 mice) and in vitro (astrocyte) models to test the hypothesis that Mn-induced lipid-droplet (LD) accumulation is a proximal trigger for A1 activation. Mn exposure activated the mTOR-p70S6K1 signaling pathway, which suppressed LAMP2 expression and disrupted the LAMP2-PLIN2 interaction required for LD autophagy. Blockade of lysosomal degradation led to LD accumulation and subsequent A1 astrocyte activation. Pharmacological inhibition of the mTOR-p70S6K1 restored LAMP2-PLIN2 coupling, accelerated LD clearance, and alleviated A1 activation. Our findings establish the mTOR-p70S6K1/PLIN2-LAMP2/LD autophagy axis as a mechanistic link between Mn exposure and astrocyte-mediated neuroinflammation, and suggest that modulating LD turnover may represent a potential therapeutic strategy against Mn-induced neurological damage.
Yuan et al. (Thu,) studied this question.