MYO6 Activates cGAS-STING Pathway in CD4+ T Cell to Accelerate Parkinson's Disease

Immunological system dysfunction has a pivotal role in the progression of Dopamine (DA) neuronal loss in Parkinson's Disease (PD), in which CD4+ T cells are key players. The cGAS-STING pathway is involved in immune modulation. We propose to clarify the specific function of this pathway in CD4+ T cells and its potential contribution to the development of the pathogenesis of PD.

We screened common differential proteins in peripheral and midbrain CD4+ T cells from PD mice by proteomic analyses and defined the common upregulated differential protein Myosin VI (MYO6) as a target protein by Protein-Protein Interaction (PPI) analysis. The expression of MYO6 and cGAS-STING pathway proteins was assayed by western blot.

The validation experiment found that the upregulation of MYO6 protein expression was accompanied by the activation of the cGAS-STING pathway, including cGAS, phosphorylated- STING (p-STING)/STING, phosphorylated-TBK1 (p-TBK1)/TBK1, and phosphorylated-IRF3 (p-IRF3)/IRF3, together with increased IL-6 and iNOS expressions in peripheral and midbrain CD4+ T cells from PD mice. Strikingly, deletion of MYO6 and TBK1 in CD4+ T cells attenuated neuroinflammation and DA neuronal death. MYO6 was a novel upstream regulator of TBK1.

Here, we determined that the MYO6-cGAS-STING-TBK1 cascade of signaling was involved in the progression of PD. MYO6 may be a potentially CD4+ T cell-associated target for the treatment of PD.