Dysregulation of bcl-2 enhanced rotenone-induced α-synuclein aggregation associated with autophagic pathways.

α-Synuclein (α-syn) aggregation has far-reaching implications in the pathogenesis of Parkinson's disease, and the levels of α-syn protein determine its neurotoxic potential. However, the intrinsic pathway of α-syn accumulation and the mode of α-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 α-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 α-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 α-syn aggregation, whereas the inhibition of autophagy by 3-methyladenine increased α-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 α-syn aggregation. In short, in rotenone-based models, dowregulation of bcl-2 negatively controlled rotenone-induced autophagy and α-syn aggregation.