Complement C4 exacerbates astrocyte-mediated neuroinflammation and promotes α-synuclein pathology in Parkinson’s disease

Complement C4, implicated in neuroinflammation and synaptic dysfunction, plays a poorly defined role in Parkinson’s disease (PD). Here, we demonstrate elevated C4 levels in PD patient plasma and the substantia nigra of α-synuclein preformed fibril (α-syn PFF)-injected mice, correlating with disease severity. α-syn PFF treatment induces complement C4 expression, particularly in neurons, with astrocytes further enhancing this response. Complement C4 was found to amplify astrocytic inflammatory responses, leading to increased neuronal apoptosis and synaptic damage. Additionally, conditioned media from astrocytes treated with α-syn PFF and complement C4 accelerated α-syn aggregation and synaptic loss in cultured neurons. In vivo, complement C4 exacerbated motor dysfunction, dopaminergic neuronal loss, and α-syn pathology in α-syn PFF-injected mice. These findings reveal that complement C4 significantly contributes to the neuroinflammatory environment and α-syn pathology in PD, highlighting its potential as a therapeutic target for mitigating neurodegeneration in this disorder.