Mitochondrial inhibitor 3-nitroproprionic acid enhances oxidative modification of alpha-synuclein in a transgenic mouse model of multiple system atrophy.
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.
Ubhi
Kiren
K
Department of Neurosciences, School of Medicine, University of California-San Diego, La Jolla, California 92093-0624, USA.
Lee
Phil Hyu
PH
Adame
Anthony
A
Inglis
Chandra
C
Mante
Michael
M
Rockenstein
Edward
E
Stefanova
Nadia
N
Wenning
Gregor K
GK
Masliah
Eliezer
E
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*
D003292:Convulsants; D004676:Myelin Basic Protein; D009566:Nitrates; D009574:Nitro Compounds; D011422:Propionates; D051844:alpha-Synuclein; C015392:3-nitropropionic acid