CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson's disease

Background The mechanisms underlying the pathogenesis and progression of Parkinson's disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to alpha-synuclein-mediated toxicity. Migration of microglia to the substantia nigra (SN) could precede neurodegeneration in A53T mice. We hypothesized that CXCL12 could be a mediator in the alpha-synuclein-induced migration of microglia. Methods After establishing appropriate animal and cell culture models, we explored the relationship between alpha-synuclein and CXCL12 in A53T mice, primary microglia, and BV-2 cell lines. We also explored the mechanisms of these interactions and the signaling processes involved in neuroinflammation. Results We confirmed the positive correlation between alpha-synuclein and CXCL12 in the postmortem brain tissue of PD patients and the upregulated CXCR4 expression in SN microglia of A53T mice. In addition, as expected, alpha-synuclein increased the production of CXCL12 in microglia via TLR4/I kappa B-alpha/NF-kappa B signaling. Importantly, CXCL12/CXCR4/FAK/Src/Rac1 signaling was shown to be involved in alpha-synuclein-induced microglial accumulation. Conclusions Our study suggests that CXCL12 could be a novel target for the prevention of alpha-synuclein-triggered ongoing microglial responses. Blocking CXCL12/CXCR4 may be a potential therapeutic approach for PD progression.