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.
Ohtake et al. (Fri,) studied this question.