Ari E. Berman and Wai Yee Chan contributed equally to this work.
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Original Article
N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1−/− mouse
Article first published online: 23 NOV 2010
DOI: 10.1002/ana.22162
Copyright © 2010 American Neurological Association
Additional Information
How to Cite
Berman, A. E., Chan, W. Y., Brennan, A. M., Reyes, R. C., Adler, B. L., Suh, S. W., Kauppinen, T. M., Edling, Y. and Swanson, R. A. (2011), N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1−/− mouse. Ann Neurol., 69: 509–520. doi: 10.1002/ana.22162
Publication History
- Issue published online: 28 MAR 2011
- Article first published online: 23 NOV 2010
- Manuscript Accepted: 13 JUL 2010
- Manuscript Revised: 3 JUL 2010
- Manuscript Received: 26 JUL 2009
Funded by
- U.S. Department of Veterans Affairs
- Michael J. Fox Foundation for Parkinson's Research
Abstract
Objective
Dopaminergic neuronal death in Parkinson's disease (PD) is accompanied by oxidative stress and preceded by glutathione depletion. The development of disease-modifying therapies for PD has been hindered by a paucity of animal models that mimic these features and demonstrate an age-related progression. The EAAC1−/− mouse may be useful in this regard, because EAAC1−/− mouse neurons have impaired neuronal cysteine uptake, resulting in reduced neuronal glutathione content and chronic oxidative stress. Here we aimed to (1) characterize the age-related changes in nigral dopaminergic neurons in the EAAC1−/− mouse, and (2) use the EAAC1−/− mouse to evaluate N-acetylcysteine, a membrane-permeable cysteine pro-drug, as a potential disease-modifying intervention for PD.
Methods
Wild-type mice, EAAC1−/− mice, and EAAC1−/− mice chronically treated with N-acetylcysteine were evaluated at serial time points for evidence of oxidative stress, dopaminergic cell death, and motor abnormalities.
Results
EAAC1−/− mice showed age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta, with more than 40% of these neurons lost by age 12 months. This neuronal loss was accompanied by increased nitrotyrosine formation, nitrosylated α-synuclein, and microglial activation. These changes were substantially reduced in mice that received N-acetylcysteine.
Interpretation
These findings suggest that the EAAC1−/− mouse may be a useful model of the chronic neuronal oxidative stress that occurs in PD. The salutary effects of N-acetylcysteine in this mouse model provide an impetus for clinical evaluation of glutathione repletion in PD. ANN NEUROL 2010