Here we show that
alpha-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-1beta and
TNF-alpha. When stimulated by
alpha-synuclein in combination with IFN-gamma, secretions from the cells also become toxic towards SH-SY5Y
neuroblastoma cells. The A30P, E46K and A53T
alpha-synuclein mutations, which induce
Parkinson's disease, are more potent than normal
alpha-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 following exposure to
alpha-synuclein, which is consistent with a receptor-mediated effect. These findings demonstrate that
alpha-synuclein acts as a potent inflammatory stimulator of microglial cells, and that inhibitors of such stimulation might be beneficial in the treatment of
Parkinson's disease and other
synucleinopathies.