Comparative analysis of T-cell signatures and astroglial reactivity in Parkinson's pathology across animal models with distinct regenerative capacities

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded α-synuclein (aSyn). Emerging evidence suggests that the immune system, particularly T-cell-mediated responses, plays a key role in the pathogenesis of PD. However, the heterogeneity of these immune responses across species and preclinical models with varying regenerative capacities remains poorly understood. In this study, we performed a comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species. These included acute DAergic degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), genetically modified mice with accumulation of aSyn (Thy1-aSyn L61 model), adult zebrafish exposed to MPTP-induced neurotoxicity and human post-mortem midbrain tissue obtained from PD patients. Zebrafish exhibited transient DAergic neurodegeneration followed by neuronal regeneration and a temporary CD4+ T-cell infiltration alongside a regulated astroglial response. In contrast, MPTP-treated mice showed a permanent neuronal loss, increased astrogliosis and CD8+ T-cell infiltration that was negatively correlated with neuronal survival. In contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis and CD4+ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains displayed DAergic degeneration, aSyn aggregation, and elevated CD3+ T-cell infiltration, which correlated with neuronal loss and aSyn burden. These findings emphasise the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4+ T-cells contribute to neuronal regeneration following injury in zebrafish. This process is absent in the MPTP and L61 mouse models, which are instead driven by CD8+ or CD4+, respectively. This work underscores the potential of targeted immunomodulation aimed at T cell - glial interactions to slow neurodegeneration and promote repair in PD.