title: Mitochondrial inhibitor 3-nitroproprionic acid enhances oxidative modification of alpha-synuclein in a transgenic mouse model of multiple system atrophy.
abstract: Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by autonomic failure, parkinsonism, cerebellar ataxia, and oligodendrocytic accumulation of alpha-synuclein (alphasyn). Oxidative stress has been linked to neuronal death in MSA and the mitochondrial toxin 3-nitropropionic acid (3NP) is known to enhance the motor deficits and neurodegeneration in transgenic mice models of MSA. However, the effect of 3NP administration on alphasyn itself has not been studied. In this context, we examined the neuropathological effects of 3NP administration in alphasyn transgenic mice expressing human alphasyn (halphasyn) under the control of the myelin basic protein (MBP) promoter and the effect of this administration on posttranslational modifications of alphasyn, on levels of total alphasyn, and on its solubility. We demonstrate that 3NP administration altered levels of nitrated and oxidized alphasyn in the MBP-halphasyn tg while not affecting global levels of phosphorylated or total alphasyn. 3NP administration also exaggerated neurological deficits in the MBP-halphasyn tg mice, resulting in widespread neuronal degeneration and behavioral impairment.
authors.affiliation: Department of Neurosciences, School of Medicine, University of California-San Diego, La Jolla, California 92093-0624, USA.
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.forename: Phil Hyu
authors.initials: PH
authors.lastname: Lee
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Chandra
authors.initials: C
authors.lastname: Inglis
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009566:Nitrates / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011422:Propionates / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism*
chemical_list: D003292:Convulsants; D004676:Myelin Basic Protein; D009566:Nitrates; D009574:Nitro Compounds; D011422:Propionates; D051844:alpha-Synuclein; C015392:3-nitropropionic acid