The autoimmune response induced by α-synuclein peptides drives neuronal cell death and glial cell activation

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic neurons and neuroinflammation. Recent studies have identified a role of T cells in the pathogenesis of PD. Additionally, these studies suggested that alpha-synuclein (alpha-Syn) is related to abnormal T-cell responses and may act as an epitope and trigger autoimmune T-cell responses. However, it is unclear whether the alpha-Syn-mediated autoimmune response occurs and whether it is related to neuronal cell death and glial cell activation. In this study, we investigated the autoimmune T-cell response induced by alpha-Syn peptides and evaluated the neurotoxic effect of the alpha-Syn peptide-mediated autoimmune response. The immunization of mice with alpha-Syn peptides resulted in enhanced autoimmune responses, such as the peptide recall response, polarization toward Th1/Th17 cells, and regulatory T cell imbalance. Furthermore, the alpha-Syn autoimmune response led to the death of primary neurons cocultured with splenocytes. Treatment with conditioned media from alpha-Syn peptide-immunized splenocytes induced microglia and toxic A1-type astrocyte activation. Taken together, our results provide evidence of the potential role of the alpha-Syn-initiated autoimmune response and its contribution to neuronal cell death and glial cell activation.