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

K. Ubhi, P. Hyu Lee, A. Adame, C. Inglis, M. Mante et al.

University of California–San Diego, School of Medicine, Department of Neurosciences and Department of Pathology, La Jolla, California ; Yonsei University College of Medicine, Department of Neurology, Seoul, South Korea ; Innsbruck Medical University, Clin

Journal of Neuroscience Research

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

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)

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