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

by Selleckchem | Sep 28 2023

Background: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accumulation of Lewy body deposits composed of alpha-Synuclein (α-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 α-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 α-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (RORγt) upregulation in α-Syn stimulation in vivo and in vitro.

Results: We found that the α-Syn level and severity of motor symptoms were positively correlated with the increase in Th17 cells and decrease in Tregs in PD patients. Moreover, α-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 α-Syn stimulation when naïve CD4+ T cells were cultured under Th17-polarizing conditions. Mechanistically, α-Syn promotes the transcription of RORC, encoding RORγt, 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 RORγt inhibitor (GSK805) in MPTP-treated mice.

Conclusion: Together, our data suggest that α-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 RORγt attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD.

Comments:

This study investigated the role of alpha-synuclein (α-Syn), a protein associated with Parkinson's disease (PD), in promoting the imbalance between T helper 17 (Th17) cells and regulatory T cells (Tregs) in PD. The researchers examined the levels of Th17 cells, Tregs, and α-Syn in the peripheral blood of PD patients, as well as in the substantia nigra pars compacta (SNpc) and spleen of mice treated with MPTP (a neurotoxin commonly used to model PD) and A53 transgenic mice (a mouse model of PD).

The results showed a positive correlation between α-Syn levels, motor symptoms severity, and the increase in Th17 cells, as well as a decrease in Tregs in PD patients. Furthermore, the researchers found that α-Syn stimulation led to the loss of FOXP3 expression (a marker of Tregs) in Tregs, accompanied by the acquisition of IL-17A expression (a cytokine produced by Th17 cells). Additionally, α-Syn stimulation promoted the differentiation of Th17 cells when naïve CD4+ T cells were cultured under conditions that promote Th17 differentiation.

The researchers investigated the underlying mechanism and found that α-Syn promotes the transcription of RORC, which encodes retinoid-related orphan nuclear receptor (ROR) γt, in both Tregs and Th17 cells. RORγt is a transcription factor that plays a crucial role in the differentiation of Th17 cells. Increased RORγt expression resulted in enhanced Th17 differentiation and loss of Treg function. Interestingly, the researchers observed that inhibiting RORγt using a specific inhibitor (GSK805) suppressed the increase in Th17 cells, decrease in Tregs, and apoptosis of dopaminergic neurons (DA) in MPTP-treated mice.

In conclusion, the findings of this study suggest that α-Syn promotes the transcription of RORγt in Tregs and Th17 cells, leading to impaired Treg stability and increased Th17 differentiation in PD. Inhibiting RORγt alleviated the imbalance between Th17 cells and Tregs and protected against the apoptosis of DA in a mouse model of PD. These findings provide insights into the immunological mechanisms underlying PD and suggest that targeting RORγt may have therapeutic potential in PD treatment.