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

Abstract

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.

Ndfip1 Prevents Rotenone-Induced Neurotoxicity and Upregulation of α-Synuclein in SH-SY5Y Cells

“…Alpha-syn aggregate is a critical event in the death of DA neurons and the progression of PD (Sanders and Greenamyre, 2013). Rotenone is an insecticide, which could inhibit complex I activity and promote α-syn up-regulation and aggregate (Betarbet et al, 2000;Sanders and Greenamyre, 2013;Chen et al, 2018). Our results also indicate that rotenone is able to increase both the mRNA and protein levels of α-syn in SH-SY5Y cells.…”

Balancing Apoptosis and Autophagy for Parkinson’s Disease Therapy: Targeting BCL-2

“…α-Synuclein aggregation increased, accompanied by reduction of BCL-2 level and blockage of autophagic flux, in dopaminergic neurons of rotenone-induced PD rats. While inhibition of BCL-2 could aggravate autophagic insults and increase rotenone-induced α-synuclein aggregation, indicating dysregulation of BCL-2 enhanced rotenone-induced neurotoxin . One study found that BAX is translocated to and internalized by lysosomes following MPTP treatment and that inhibiting BAX could restore lysosomal function and reverse autophagosome accumulation, suggesting that BAX contributes to lysosomal disruption in MPTP-induced PD models .…”

“…While inhibition of BCL-2 could aggravate autophagic insults and increase rotenone-induced α-synuclein aggregation, indicating dysregulation of BCL-2 enhanced rotenone-induced neurotoxin. 106 One study found that BAX is translocated to and internalized by lysosomes following MPTP treatment and that inhibiting BAX could restore lysosomal function and reverse autophagosome accumulation, suggesting that BAX contributes to lysosomal disruption in MPTP-induced PD models. 107 Restoring autophagy through modulation of BCL-2 is another potential therapeutic strategy for PD treatment.…”

Fenofibrate promotes neuroprotection in a model of rotenone-induced Parkinson’s disease

“…The rotenone model stands out from other toxin-based models by replicating almost all the features of Parkinson’s disease including α-synuclein aggregation and Lewy-like body formation (Sherer et al , 2003; Yuan et al , 2015; Chen et al , 2018). Among the toxic animal models of Parkinson’s disease, rotenone represents one of the most used approaches.…”