A GLUD2 variant aggravates Parkinson’s disease pathology in A53T α-synuclein mice via the astrocyte–microglia C3‒C3aR pathway

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and α-synuclein (α-syn) aggregation. The human-specific GLUD2 T1492G variant has been associated with an earlier onset of PD, but its pathogenic mechanism remains unclear. In this study, we generated A53T α-syn transgenic mice with astrocyte-specific expression of GLUD2 T1492G and investigated its effects on PD-related pathology. GLUD2 T1492G exacerbated α-syn pathology, nigrostriatal dopaminergic neurodegeneration, and motor impairment. Transcriptomic analysis identified complement-related inflammatory signaling as a major pathway altered by GLUD2 T1492G, whereas metabolomic profiling revealed disrupted metabolic homeostasis. Mechanistically, GLUD2 T1492G enhanced astrocytic C3 induction, promoted microglial C3aR/NF-κB-associated inflammatory activation, and amplified neuroinflammatory responses. Conditioned-medium transfer experiments, together with astrocyte-specific C3 knockdown and pharmacological inhibition of C3aR, supported the functional involvement of the astrocyte–microglia C3–C3aR signaling axis in GLUD2 T1492G-associated pathology. Collectively, our findings suggest that activation of the astrocyte–microglia C3–C3aR signaling axis contributes to GLUD2 T1492G-mediated exacerbation of PD pathology and highlight this pathway as a potential therapeutic target for PD.