Microglia-T cell interactions drive α-synuclein pathology in a Parkinson's disease mouse model.

Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, is characterized by motor dysfunction, progressive dopaminergic (DA) neuron loss in the substantia nigra, and the pathological accumulation of α-synuclein (αSyn) aggregates within Lewy bodies. Emerging evidence suggests that neuroinflammation and adaptive immunity may contribute to PD pathogenesis. To investigate the underlying mechanisms, we adapted a PD model combining AAV-mediated αSyn overexpression with intranigral injection of αSyn fibrils, which enabled us to analyze the temporal sequence of pathological and immune responses over a defined time course. The model recapitulated key features of PD, including αSyn phosphorylation, motor deficits, and nigral DA neurodegeneration, alongside early-stage microglial activation and T cell infiltration. Furthermore, T cell deficiency markedly reduced these pathological changes and attenuated microglial activation, and pharmacological depletion of microglia suppressed T cell accumulation in the brain and mitigated PD pathology. Notably, microglia-associated chemokine induction remained detectable despite T cell deficiency, whereas pro-inflammatory cytokine induction was attenuated, suggesting amplification of neuroinflammation through T cell–microglia interactions. These findings underscore the crucial role of T cell–microglia crosstalk in accelerating PD pathogenesis, and suggest that targeting this early immune–glial interplay may help mitigate PD-related neuroinflammation and neuronal degeneration.