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[alpha]-Synuclein has been implicated in the pathogenesis of Parkinson's disease (PD). Previous studies have shown that [alpha]-synuclein is involved in the regulation of dopamine (DA) metabolism, possibly by down-regulating the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in DA biosynthesis. In this study, we constructed [alpha]-synuclein stably silenced MN9D/[alpha]-SYN- cells by vector mediated RNA interference and examined its effects on DA metabolism. We found that there were no significant differences in TH protein and mRNA levels between MN9D, MN9D/[alpha]-SYN- and MN9D/CON cells, suggesting that silencing [alpha]-synuclein expression does not affect TH gene expression. However, significant increases in phosphorylated TH, cytosolic 3, 4-dihydroxyphenylalanine (L-DOPA) and DA levels were observed in MN9D/[alpha]-SYN- cells. Our data show that TH activity and DA biosynthesis were enhanced by down-regulation of [alpha]-synuclein, suggesting that [alpha]-synuclein may act as a negative regulator of cytosolic DA. With respect to PD pathology, a loss of functional [alpha]-synuclein may result in increased DA levels in neurons that may lead to cell injury or even death.

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