Potential role of splice junctions of α-synuclein isoforms in the activation of T-cells: Implications for Parkinson's disease.

α-Synuclein (α-syn) aggregate-mediated loss of dopaminergic neurons play a critical role in the mechanisms mediating Parkinson's disease (PD). While neuroinflammation is invariably associated with several neurodegenerative disorders, emerging reports on the N- and C-terminus epitopes of α-syn in inducing activated T-cells/microglia garnered much attention. Interestingly, differential expression of isoforms of α-syn with altered N- and C-terminus regions were also noticed in PD subjects; however, their role in the activation of T-cells is not yet known. Hence, we sought to investigate the effect of monomeric and aggregated α-syn-spliced isoforms on activation of T-cells. Our results indicate that, as compared to monomeric forms, stereotaxic administration of PFFs of Wild Type (WT-syn) and 112-syn-induced significant loss of SNPc dopamine neurons and motor coordination. Further, the expression of CD4+ and CD8+ T-cells was significantly elevated by PFFs of WT and 112-syn as compared to their corresponding monomers. Peripheral blood mononuclear cells (PBMCs) isolated from mice administered with PFFs exhibited increased cytokine responses upon stimulation with peptides corresponding to the C-terminus region of WT-syn and 112-syn, suggesting their antigenic potential in the order WT-syn < 112-syn. This enhanced antigenicity of 112-syn indicate that the spliced α-syn isoforms, particularly 112-syn, could play a critical role in immune activation in PD, highlighting splice junctions as potential targets for therapeutic strategies.