Alpha-synuclein induces microglial migration via PKM2-dependent glycolysis

After spinal cord injury, microglial cells are activated and converted to an M1 phenotype. Emerging evidence supports the hypothesis that glucose reprogramming accompanies microglial activation. What contributes to the activation of microglia and glucose reprogramming, however, remains unclear. In the current study, we investigated the role and underlying mechanism of a-synuclein in regulating the aerobic glycolysis in microglia. We found that a-synuclein contributed to the reprogramming of glucose metabolism in microglia by promoting glycolysis and inhibiting mitochondrial biogenesis and oxidative phosphorylation. Further studies demonstrated that pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis, mediated glucose reprogramming regulated by a-synuclein. A co-immunoprecipitation assay and Western blot assay demonstrated that a-synuclein interacted with PKM2. Further studies demonstrated that knockdown of PKM2 in a-synuclein-exposed microglia markedly reduced glycolysis and lactate production. Additionally, a-synuclein exposure promoted migration abilities in glucose-cultured microglia, whereas migration ability was suppressed in PKM2 knockdown microglia. Additionally, the PKM2 activator TEPP-46 promoted migration ability in a-synuclein-treated microglia, compared to treatment with a-synuclein alone. In conclusion, we demonstrate a PKM2-dependent glycolysis of a-synuclein in microglial.