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Mitochondrial inhibitor 3‐nitroproprionic acid enhances oxidative modification of alpha‐synuclein in a transgenic mouse model of multiple system atrophy
Author(s) -
Ubhi Kiren,
Lee Phil Hyu,
Adame Anthony,
Inglis Chandra,
Mante Michael,
Rockenstein Edward,
Stefanova Nadia,
Wenning Gregor K.,
Masliah Eliezer
Publication year - 2009
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22089
Subject(s) - neurodegeneration , genetically modified mouse , parkinsonism , oxidative stress , transgene , alpha synuclein , atrophy , ataxia , myelin , biology , parkinson's disease , microbiology and biotechnology , neuroscience , medicine , endocrinology , biochemistry , central nervous system , disease , gene , genetics
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. © 2009 Wiley‐Liss, Inc.