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Here we show that α-synuclein, a major constituent of Lewy bodies, induces inflammation in human microglial and human THP-1 cells. Secretions from such stimulated THP-1 cells contain increased levels of IL-1β and TNF-α. When stimulated by α-synuclein in combination with IFN-γ, secretions from the cells also become toxic towards SH-SY5Y neuroblastoma cells. The A30P, E46K and A53T α-synuclein mutations, which induce Parkinson's disease, are more potent than normal α-synuclein in the induction of such cytotoxicity. To investigate the signaling mechanisms evoked, protein phosphorylation profiling was applied. At least 81 target phospho-sites were identified. Large increases were induced in the three major mitogen-activated protein (MAP) kinase pathways: p38 MAP kinase, extracellular regulated protein-serine kinase (ERK)1/2 and c-Jun-N-terminal kinase (JNK). Upregulation occurred within minutes …