title: Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson's disease.
abstract: Brain mononuclear phagocyte (perivascular macrophage and microglia, MG) inflammatory neurotoxins play a principal role in the pathogenesis of Parkinson's disease; chief among these are reactive oxygen species (ROS). We posit that aggregated, misfolded and oxidized alpha-synuclein (a major constituent of Lewy bodies), released or secreted from dying dopaminergic neurons, induces microglial ROS production that is regulated by ion channels and as such affects disease progression. To address this hypothesis, we performed patch clamp recordings of outward ionic currents in murine microglia and characterized their links to ROS production during alpha-synuclein stimulation. Aggregated nitrated alpha-synuclein induced ROS production in a dose-dependent manner that was inhibited by voltage-gated potassium current blockade, and to a more limited degree, by chloride current blockade. Interestingly, ROS produced in MG primed with tumor necrosis factor alpha and activated with phorbol myristate acetate was attenuated by voltage-gated potassium current blockade and more completely by chloride current blockade. In contrast, amyloid beta or cell membrane extract failed to induce microglial ROS production. Similar results were obtained using bone marrow-derived macrophages. The association of ROS production with specific plasma membrane ion currents provides a link between regulation of microglial ion transport and oxygen free radical production. Understanding these linkages may lead to novel therapeutics for Parkinson's disease where modulation of redox-related stress may slow disease progression.
authors.affiliation: Laboratory of Neuroregeneration, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA. hegendel@unmc.edu
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chartrand
authors.forename: Ashley
authors.initials: A
authors.lastname: Reynolds
authors.forename: Victor
authors.initials: V
authors.lastname: Vitvitsky
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D018999:Charybdotoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology; D051844:alpha-Synuclein / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C481395:4-aminopiperidine; D007473:Ion Channels; D009498:Neurotoxins; D010880:Piperidines; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D018999:Charybdotoxin; D015032:Zinc