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). In addition to neuronal pathology, activated microglia are recognized as key mediators of the neuroinflammatory milieu in PD, con- tributing to DAergic neuron vulnerability. 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. A comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species was performed. 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. Ze- brafish exhibited transient DAergic neurodegeneration, followed by neuronal regeneration and temporary CD4+ T-cell infiltration accompanied by an astroglial response and acti- vation of microglia. In contrast, MPTP-treated mice showed a permanent neuronal loss, marked microglial activation, increased astrogliosis and CD8+ T-cell infiltration that was negatively correlated with neuronal survival. By contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis, mild activation of microglia and CD4+ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains exhibited DAergic degeneration, aSyn aggregation, and elevated CD3+ T-cell infiltration, and increased microglial activation. These changes correlated with neuronal loss and aSyn burden. These findings emphasize the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4+ T-cells contribute to neu- ronal 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.