alpha-Synuclein affects the MAPK pathway and accelerates cell death.
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.
Iwata
A
A
Laboratory for CAG Repeat Diseases, Molecular Neuropathology Group, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Maruyama
M
M
Kanazawa
I
I
Nukina
N
N
D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D017209:Apoptosis; D015152:Blotting, Northern; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015723:Gene Library; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051843:Synucleins; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry; D051844:alpha-Synuclein
D048948:14-3-3 Proteins; D002070:Butadienes; D004396:Coloring Agents; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D009570:Nitriles; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; D051843:Synucleins; D013778:Tetrazolium Salts; D013844:Thiazoles; C113580:U 0126; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D005982:Glutathione Transferase; C022616:thiazolyl blue