Dopamine and Paraquat Enhance α-Synuclein-Induced Alterations in Membrane Conductance

Abstract

We have previously demonstrated that α-synuclein overexpression increases the membrane conductance of dopaminergic-like cells. Although α-synuclein is thought to play a central role in the pathogenesis of several neurodegenerative diseases including Parkinson’s disease, multiple system atrophy and diffuse Lewy body disease the mechanism of action is not completely understood. In this study we sought to determine whether multiple factors act together with α-synuclein to engender cell vulnerability through an augmentation of membrane conductance. Here we employed a cell model that mimics dopaminergic neurons coupled with α-synuclein overexpression and oxidative stressors. We demonstrate an enhancement of α-synuclein-induced toxicity in the presence of combined treatment with dopamine and paraquat, two molecules known to incite oxidative stress. In addition we show that combined dopamine and paraquat treatment increases the expression of heme oxygenase-1, an antioxidant response protein. Finally, we demonstrate for the first time that combined treatment of dopaminergic cells with paraquat and dopamine enhances α-synuclein-induced leak channel properties resulting in increased membrane conductance. Importantly, these increases are most robust when both paraquat and dopamine are present suggesting the need for multiple oxidative insults to augment α-synuclein-induced disruption of membrane integrity.

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

“…2); this is consistent with previous data showing that α-syn and exposure to paraquat can synergistically lead to DAergic degeneration [27, 28, 69]. Additionally, TH immunoreactivity and hyperactivity was reduced in dependence of the paraquat-induced olfactory cell-death in A30P mice, thus further indicating a potential regulative role of the OB in the higher reactive phenotype.…”

Parkinson’s Disease

“…Paraquat has been extensively studied both in vitro ( e.g . Yang and Tiffany-Castiglioni 2007; Choi et al 2008; Feng and Maguire-Zeiss 2011) and in vivo ( e.g . Brooks et al 1999; Manning-Bog et al 2001, 2002; Norris et al 2007)).…”

“…Brooks et al 1999; Manning-Bog et al 2001, 2002; Norris et al 2007)). While paraquat exposure has not been shown to foster Lewy body formation, it does accelerate α-synuclein misfolding (Uversky et al 2001), enhances membrane conductance disruption with dopamine (Feng and Maguire-Zeiss 2011) or proteasome disruption (Yang and Tiffany-Castiglioni 2007) in α-synuclein overexpressing cell lines and accelerates protein aggregation, inclusion formation and neuronal degeneration in transgenic mice that over-express α-synuclein (Manning-Bog et al 2002; Fernagut et al 2007; Peng et al 2010). Rotenone similarly enhances α-synuclein fibril formation in in vitro systems, while it increases α-synuclein modification, misfolding and toxicity in cultured cells (Orth et al 2003; Mirzaei et al 2006; Borland et al 2008; Lu et al 2010; Ma et al 2011).…”

Paraquat: Molecular Mechanisms of Neurotoxicity and its Relation with Autophagy

“…a-synuclein overexpression induces the formation of membrane pore-like structures that increase membrane conductance [54]. Co-exposure with PQ and dopamine enhances a-synuclein -induced leak channel conductivity, leading to a disruption of ionic imbalance, and eventually dopaminergic cell death [55]. In vivo experiments have corroborated these results, showing that PQ treatment induces the accumulation of a-synuclein and hyperphosphorylation of Tau within the specific sites of phosphorylation found in PD post mortem striata [56,57].…”