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

Modulation of the neuroinflammatory response is emerging as an interesting approach for the treatment of Parkinson´s disease (PD). In this study we have used an adeno-associated virus (AAV9) to overexpress alpha-synuclein (αSyn) in the substantia nigra pars compacta of mice to induce a dose-dependent neuronal loss. Our results show that αSyn overexpression induces CD4 ⁺ T cell infiltration with a Th1 (IFNγ ⁺ TNFα ⁺ ) phenotype in the ventral midbrain. Inhibiting T cell infiltration with fingolimod (FTY720) or blocking soluble TNF signaling with XPro1595 improved motor function and preserved dopaminergic neurons. These treatments showed therapeutic efficacy in a chronic mouse model generated with lower AAV9 titers, highlighting the potential of targeting neuroinflammation for the treatment of PD. Our findings suggest that CD4 ⁺ T cells contribute to αSyn-induced neurodegeneration and that immune modulation may be a viable therapeutic strategy and support further exploration of neuroinflammation-targeting therapies in PD.