RRC ID 12068
Author Iwata A, Maruyama M, Kanazawa I, Nukina N.
Title alpha-Synuclein affects the MAPK pathway and accelerates cell death.
Journal J. Biol. Chem.
Abstract Insoluble alpha-synuclein accumulates in Parkinson's disease, diffuse Lewy body disease, and multiple system atrophy. However, the relationship between its accumulation and pathogenesis is still unclear. Recently, we reported that overexpression of alpha-synuclein affects Elk-1 phosphorylation in cultured cells, which is mainly performed by mitogen-activated protein kinases (MAPKs). We further examined the relationship between MAPK signaling and the effects of alpha-synuclein expression on ecdysone-inducible neuro2a cell lines and found that cells expressing alpha-synuclein had less phosphorylated MAPKs. Moreover, they showed significant cell death when the concentration of serum in the culture medium was reduced. Under normal serum conditions, the addition of the MAPK inhibitor U0126 also caused cell death in alpha-synuclein-expressing cells. Transfection of constitutively active MEK-1 resulted in MAPK phosphorylation in alpha-synuclein-expressing cells and improved cell viability even under reduced serum conditions. Thus, we conclude that alpha-synuclein regulates the MAPK pathway by reducing the amount of available active MAPK. Our findings suggest a mechanism for pathogenesis and thus offer therapeutic insight into synucleinopathies.
Volume 276(48)
Pages 45320-9
Published 2001-11-30
DOI 10.1074/jbc.M103736200
PII M103736200
PMID 11560921
MeSH 14-3-3 Proteins Amino Acid Sequence Apoptosis Blotting, Northern Butadienes / pharmacology Cell Death* Cell Line Cell Survival Coloring Agents / pharmacology DNA, Complementary / metabolism Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Gene Library Glutathione Transferase / metabolism Humans Immunoblotting Immunohistochemistry In Situ Nick-End Labeling MAP Kinase Signaling System* Molecular Sequence Data Mutation Nerve Tissue Proteins / metabolism* Nerve Tissue Proteins / physiology* Nitriles / pharmacology Phosphorylation Plasmids / metabolism Precipitin Tests Protein Binding Recombinant Fusion Proteins / metabolism Sequence Homology, Amino Acid Signal Transduction Synucleins Tetrazolium Salts / pharmacology Thiazoles / pharmacology Time Factors Transfection Tyrosine 3-Monooxygenase / chemistry alpha-Synuclein
IF 4.106
Times Cited 100
DNA material pZRmERK2 (RDB01796)