α-Synuclein Affects the MAPK Pathway and Accelerates Cell Death*

Insoluble α-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 α-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 α-synuclein expression on ecdysone-inducible neuro2a cell lines and found that cells expressing α-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 α-synuclein-expressing cells. Transfection of constitutively active MEK-1 resulted in MAPK phosphorylation in α-synuclein-expressing cells and improved cell viability even under reduced serum conditions. Thus, we conclude that α-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.