title: UCP2 overexpression worsens mitochondrial dysfunction and accelerates disease progression in a mouse model of amyotrophic lateral sclerosis.
abstract: Mitochondrial dysfunction leading to deficits in energy production, Ca(2+) uptake capacity, and free radical generation has been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) caused by mutations in Cu,Zn superoxide dismutase (SOD1). Numerous studies link UCP2, a member of the uncoupling protein family, to protection of neurons from mitochondrial dysfunction and oxidative damage in various mouse models of acute stress and neurodegeneration, including Parkinson's disease. Here, we tested the potential neuroprotective effects of UCP2 and its ability to modulate mitochondrial function, in the G93A mutant SOD1 mouse model of familial ALS. Disease phenotype, mitochondrial bioenergetics, and Ca(2+) uptake capacity were investigated in the central nervous system of double transgenic mice, expressing both human mutant G93A SOD1 and human UCP2 (hUCP2). Unexpectedly, hUCP2 expression accelerated the disease course of SOD1 mutant mice. In addition, we did not observe a classical uncoupling effect of hUCP2 in G93A brain mitochondria, although we did detect a decrease in reactive oxygen species (ROS) production from mitochondria challenged with the respiratory chain inhibitors rotenone and antimycin A. We also found that mitochondrial Ca(2+) uptake capacity was decreased in the double transgenic mice, as compared to G93A mice. In summary, our results indicate that the neuroprotective role of UCP2 in neurodegeneration is disease-specific and that, while a mild uncoupling by UCP2 in brain mitochondria may protect against neurodegeneration in some injury paradigms, the mitochondrial damage and the disease caused by mutant SOD1 cannot be ameliorated by UCP2 overexpression.
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st St, New York, NY 10065, USA; Department of Natural Sciences, Baruch College, City University of New York (CUNY), 17 Lexington Avenue, New York, NY 10010, USA.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Peixoto
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Brittany
authors.initials: B
authors.lastname: Sider
authors.forename: Anatoly
authors.initials: A
authors.lastname: Starkov
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D014475:Uncoupling Agents / Q000494:pharmacology; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D012402:Rotenone; D000968:Antimycin A; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium
keywords: ALS; CNS; Mitochondria; ROS; RQ; SOD1; UCP2; amyotrophic lateral sclerosis; central nervous system; hUCP2; human uncoupling protein 2; non-transgenic; ntg; reactive oxygen species; respiratory quotient; superoxide dismutase 1