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Dysregulation of bcl-2 enhanced rotenone-induced &agr;-synuclein aggregation associated with autophagic pathways

&agr;-Synuclein (&agr;-syn) aggregation has far-reaching implications in the pathogenesis of Parkinson’s disease, and the levels of &agr;-syn protein determine its neurotoxic potential. However, the intrinsic pathway of &agr;-syn accumulation and the mode of &agr;-syn degradation remain contentious. Following a stereotactic infusion of rotenone into the substantia nigra and the ventral tegmental area, the chronic rat model of Parkinson’s disease was established successfully. In response to the rotenone, increased intracellular &agr;-syn levels and autophagic flux monitored by LC3 II turnover were induced in dopaminergic neurons (TH-positive) of rat substantia nigra and ventral tegmental area. In the cytoplasm, increased immune response of LC3 colocalized with &agr;-syn on the basis of rotenone-mediated neurotoxicity. The immunoreactivity for p62, an adaptor of the autophagy, was upregulated in the cytoplasm and nucleus. The enhancement of autophagy by valproate acid decreased rotenone-induced &agr;-syn aggregation, whereas the inhibition of autophagy by 3-methyladenine increased &agr;-syn aggregation. In addition, the expression of bcl-2 was reduced in rotenone-induced neurotoxicity, accompanied by the enhancement of autophagy. Small interfering RNA-mediated knockdown of bcl-2 expression facilitated the expression of p62 protein and autophagy. Moreover, the inhibition of bcl-2 increased rotenone-based &agr;-syn aggregation. In short, in rotenone-based models, dowregulation of bcl-2 negatively controlled rotenone-induced autophagy and &agr;-syn aggregation.