?-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson?s disease

Background: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accu-mulation of Lewy body deposits composed of alpha-Synuclein (alpha-Syn), which act as antigenic epitopes to drive cytotoxic T-cell responses in PD. Increased T helper 17 (Th17) cells and dysfunctional regulatory T cells (Tregs) have been reported to be associated with the loss of DA in PD. However, the mechanism underlying the Th17/ Treg imbalance remains unknown.Methods: Here, we examined the percentage of Th17 cells, the percentage of Tregs and the alpha-Syn level and analysed their correlations in the peripheral blood of PD patients and in the substantia nigra pars compacta (SNpc) and spleen of MPTP-treated mice and A53 transgenic mice. We assessed the effect of alpha-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (ROR gamma t) upregulation in alpha-Syn stimulation in vivo and in vitro.Results: We found that the alpha-Syn level and severity of motor symptoms were positively correlated with the in-crease in Th17 cells and decrease in Tregs in PD patients. Moreover, alpha-Syn stimulation led to the loss of Forkhead box protein P3 (FOXP3) expression in Tregs, accompanied by the acquisition of IL-17A expression. Increased Th17 differentiation was detected upon alpha-Syn stimulation when naive CD4+ T cells were cultured under Th17-polarizing conditions. Mechanistically, alpha-Syn promotes the transcription of RORC, encoding ROR gamma t, in Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg function. Intriguingly, the increase in Th17 cells, decrease in Tregs and apoptosis of DA were suppressed by a ROR gamma t inhibitor (GSK805) in MPTP-treated mice.Conclusion: Together, our data suggest that alpha-Syn promotes the transcription of RORC in circulating CD4+ T cells, including Tregs and Th17 cells, to impair the stability of Tregs and promote the differentiation of Th17 cells in PD. Inhibition of ROR gamma t attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD.

Automated summary

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons and accumulation of alpha-Synuclein (alpha-Syn). Th17 cells and dysfunctional regulatory T cells (Tregs) are associated with the loss of dopaminergic neurons in PD. The mechanism underlying the Th17/Treg imbalance remains unknown.