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 (alpha syn). 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 alpha syn itself has not been studied. In this context, we examined the neuropathological effects of 3NP administration in alpha syn transgenic mice expressing human alpha syn (h alpha syn) under the control of the myelin basic protein (MBP) promoter and the effect of this administration on posttranslational modifications of alpha syn, on levels of total alpha syn, and on its solubility. We demonstrate that 3NP administration altered levels of nitrated and oxidized alpha syn in the MBP-h alpha syn tg while not affecting global levels of phosphorylated or total alpha syn. 3NP administration also exaggerated neurological deficits in the MBP-h alpha syn tg mice, resulting in widespread neuronal degeneration and behavioral impairment. (C) 2009 Wiley-Liss, Inc.