Mitochondrial inhibitor 3-nitroproprionic acid enhances oxidative modification of alpha-synuclein in a transgenic mouse model of multiple system atrophy

Kiren Ubhi, Hyu Lee Phil, Anthony Adame, Chandra Inglis, Michael Mante, Edward Rockenstein, Nadia Stefanova, Gregor K. Wenning, Eliezer Masliah

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60 Citations (Scopus)

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by autonomic failure, parkinsonism, cerebellar ataxia, and oligodendrocytic accumulation of alpha-synuclein (αsyn). 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 αsyn itself has not been studied. In this context, we examined the neuropathological effects of 3NP administration in αsyn transgenic mice expressing human αsyn (hαsyn) under the control of the myelin basic protein (MBP) promoter and the effect of this administration on posttranslational modifications of αsyn, on levels of total αsyn, and on its solubility. We demonstrate that 3NP administration altered levels of nitrated and oxidized αsyn in the MBP-hαsyn tg while not affecting global levels of phosphorylated or total αsyn. 3NP administration also exaggerated neurological deficits in the MBP-hαsyn tg mice, resulting in widespread neuronal degeneration and behavioral impairment.

Original languageEnglish
Pages (from-to)2728-2739
Number of pages12
JournalJournal of Neuroscience Research
Volume87
Issue number12
DOIs
Publication statusPublished - 2009 Sep 1

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All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

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