کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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331278 | 1433646 | 2008 | 14 صفحه PDF | دانلود رایگان |
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 following exposure to α-synuclein, which is consistent with a receptor-mediated effect. These findings demonstrate that α-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.
Journal: Neurobiology of Aging - Volume 29, Issue 5, May 2008, Pages 739–752