Microglial cGAS-STING-C1q axis mediates dopaminergic synaptic pruning and motor dysfunction in Mn-induced neurodegeneration.
Environmental manganese (Mn) overexposure is a recognized risk factor for Parkinsonian-like neurodegeneration. Although synaptic loss is a crucial pathological hallmark of Mn neurotoxicity, the underlying cellular and molecular mechanisms are not fully understood. We demonstrate that Mn exposure induces motor dysfunction through aberrant microglial-mediated synaptic pruning. Pharmacological depletion of microglia effectively restores synaptic density and ameliorates motor deficits, establishing microglia as the primary drivers of this synaptic pathology. Mechanistically, Mn2 + activates the cGAS-STING pathway in microglia, which orchestrates the secretion of complement factor C1q and initiates the C1q/C3-CR3 complement cascade. This neuroimmune signaling results in complement-dependent tagging of dopaminergic synapses, triggering their targeted engulfment by activated microglia and consequent synaptic loss. Notably, blocking the STING pathway or neutralizing C1q function significantly attenuated excessive synaptic phagocytosis and prevented dopaminergic synapse loss, rescuing motor dysfunction in Mn-exposed mice. Together, our findings identify the cGAS-STING-C1q axis as a critical molecular driver of pathological synaptic pruning, highlighting a potential therapeutic strategy for treating neurological dysfunction in Mn-induced Parkinsonism.