Thomas, Mark, Chartrand, Kathryn P., Reynolds, Ashley, Vitvitsky, Victor, and Gendelman, Howard E. (2007) Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance forthe pathogenesis of Parkinson’s disease. Journal of Neurochemistry, 100 (2). pp. 503-519.

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Abstract

Brain mononuclear phagocyte (perivascular macrophage andmicroglia, MG) inflammatory neurotoxins play a principal rolein the pathogenesis of Parkinson’s disease; chief amongthese are reactive oxygen species (ROS). We posit thataggregated, misfolded and oxidizeda-synuclein (a majorconstituent of Lewy bodies), released or secreted from dyingdopaminergic neurons, induces microglial ROS productionthat is regulated by ion channels and as such affects diseaseprogression. To address this hypothesis, we performed patchclamp recordings of outward ionic currents in murine microgliaand characterized their links to ROS production duringa-synuclein stimulation. Aggregated nitrateda-synuclein in-duced ROS production in a dose-dependent manner that wasinhibited by voltage-gated potassium current blockade, and toa more limited degree, by chloride current blockade. Inter-estingly, ROS produced in MG primed with tumor necrosisfactor alpha and activated with phorbol myristate acetate wasattenuated by voltage-gated potassium current blockade andmore completely by chloride current blockade. In contrast,amyloid beta or cell membrane extract failed to inducemicroglial ROS production. Similar results were obtainedusing bone marrow-derived macrophages. The association ofROS production with specific plasma membrane ion currentsprovides a link between regulation of microglial ion transportand oxygen free radical production. Understanding theselinkages may lead to novel therapeutics for Parkinson’sdisease where modulation of redox-related stress may slowdisease progression.Keywords:chloride, macrophage, mice, potassium, proton,a-synuclein.

Item ID:	80251
Item Type:	Article (Research - C1)
ISSN:	1471-4159
Keywords:	chloride, macrophage, mice, potassium, proton, a-synuclein
Copyright Information:	© 2006 The Authors. Journal Compilation © 2006 International Society for Neurochemistry.
Date Deposited:	04 Sep 2023 23:37
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320902 Cellular nervous system @ 50% 32 BIOMEDICAL AND CLINICAL SCIENCES > 3209 Neurosciences > 320905 Neurology and neuromuscular diseases @ 50%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200104 Prevention of human diseases and conditions @ 40% 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 60%
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