Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia.
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.
Klegeris
Andis
A
Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
Pelech
Steven
S
Giasson
Benoit I
BI
Maguire
John
J
Zhang
Hong
H
McGeer
Edith G
EG
McGeer
Patrick L
PL
D002460:Cell Line; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D017628:Microglia / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D018384:Oxidative Stress / Q000276:immunology*; D011494:Protein Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051844:alpha-Synuclein / Q000276:immunology*
D007155:Immunologic Factors; D047908:Intracellular Signaling Peptides and Proteins; D051844:alpha-Synuclein; D011494:Protein Kinases