title: 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. In this article, 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.
authors: Department of Neuroscience and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC 20057, USA.
authors: Li Rebekah
authors: LR
authors: Feng
authors: Kathleen A
authors: KA
authors: Maguire-Zeiss
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor / Q000166:cytology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004318:Doxycycline / Q000378:metabolism; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006540:Herbicides / Q000494:pharmacology*; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D010269:Paraquat / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010539:Permeability / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D006540:Herbicides; D009419:Nerve Tissue Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; D007980:Levodopa; D051547:Heme Oxygenase-1; D014446:Tyrosine 3-Monooxygenase; C022616:thiazolyl blue; D004318:Doxycycline; D010269:Paraquat; D004298:Dopamine