Inhibition of T cell infiltration and soluble TNF signaling is neuroprotective in the alpha-synuclein overexpressing mouse model of Parkinson’s disease

Modulating the neuroinflammatory response is an emerging and interesting approach for treating Parkinson's disease (PD). In this study, we used an adeno-associated virus (AAV9) to overexpress alpha-synuclein (αSyn) in the substantia nigra pars compacta of mice, inducing a dopaminergic degeneration in a dose-dependent manner. αSyn overexpression was associated with CD4⁺ T cell infiltration exhibiting a Th1 (IFNγ⁺TNFα⁺) phenotype in the ventral midbrain. In a chronic model induced with a low viral dose, treatment with either fingolimod (FTY720), which prevents T cell infiltration, or XPro1595, a selective inhibitor of soluble TNF signaling, led to improved motor function and resulted in partially protected dopaminergic cell bodies. These effects were not observed when an acute lesion was induced with a high viral dose. Our results support the contribution of CD4⁺ T cells to αSyn-induced neurodegeneration and suggest that immune modulation can provide neuroprotection in chronic neurodegenerative conditions, offering a wider therapeutic window. Further studies are needed to determine the optimal timing and conditions for implementing immunomodulatory strategies in PD.