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

作者：Feng Li Rebekah; Maguire Zeiss Kathleen A^*

来源：Neurotoxicity Research, 2011, 20(4): 387-401.

DOI：10.1007/s12640-011-9255-x

• Parkinson's disease
• Oxidative stress
• Pore
• Leak channel
• Dopamine
• Paraquat

We have previously demonstrated that alpha-synuclein overexpression increases the membrane conductance of dopaminergic-like cells. Although alpha-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 alpha-synuclein to engender cell vulnerability through an augmentation of membrane conductance. In this article, we employed a cell model that mimics dopaminergic neurons coupled with alpha-synuclein overexpression and oxidative stressors. We demonstrate an enhancement of alpha-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 alpha-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 alpha-synuclein-induced disruption of membrane integrity.

• 出版日期2011-11