Identification of the amino acid sequence motif of α-synuclein responsible for macrophage activation

α-Synuclein (Syn) is implicated in the pathogenesis of PD and related neurodegenerative disorders. Recent studies have also shown that α-synuclein can activate microglia and enhance dopaminergic neurodegeneration. The mechanisms of microglia activation by α-synuclein, however, are not well understood. In this study, we found that not only α-synuclein but also β- and γ-synucleins activated macrophages (RAW 264.7) in vitro. Macrophages treated with synuclein proteins secreted TNF-α in a dose-dependent manner. Synuclein family proteins also increased mRNA transcription of COX-2 and iNOS. Two α-synuclein deletion mutants, SynΔNAC and Syn61–140, activated macrophages, while deletion mutants Syn1–60 and Syn96–140 did not significantly activate them. Finally, we demonstrated that macrophage activation by α-synuclein was accompanied by phosphorylation of ERK. These results suggest that synuclein family proteins can activate macrophages, and that macrophage activation needs both the N-terminal and C-terminal domains of α-synuclein, but not the central NAC region.