Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia.
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| Abstract |
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.
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| Authors | Andis Klegeris, Steven Pelech, Benoit I Giasson, John Maguire, Hong Zhang, Edith G McGeer, Patrick L McGeer |
| Journal | Neurobiology of aging (Neurobiol Aging) Vol. 29 Issue 5 Pg. 739-52 (May 2008) ISSN: 1558-1497 [Electronic] United States |
| PMID | 17166628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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