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Neurology 2002;59:729-734
© 2002 American Academy of Neurology

Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity

M. E. Cudkowicz, MD, MSc, K. A. Pastusza, BA, P. C. Sapp, BA, R. K. Mathews, BA, J. Leahy, BA, P. Pasinelli, PhD, J. W. Francis, PhD, D. Jiang, PhD, J. K. Andersen, PhD and R. H. Brown, Jr., DPhil, MD

From the Day Neuromuscular Laboratory (Drs. Cudkowicz, Pasinelli, Francis, and Brown, and K. Pastusza, P. Sapp, R. Mathews, and J. Leahy), Department of Neurology (Drs. Cudkowicz and Brown), Neurology Clinical Trials Unit (Dr. Cudkowicz), Massachusetts General Hospital, Harvard Medical School, Boston, MA; Division of Neurogerontology (Drs. Jiang and Andersen), Andrus Gerontology Center and Program in Neurobiology, University of Southern California, Los Angeles; and Buck Institute for Age Research (Dr. Andersen), Novato, CA.

Address correspondence and reprint requests to Dr. Merit Cudkowicz, Neurology Clinical Trials Unit, Massachusetts General Hospital, 15 Parkman Street, ACC 836, Boston, MA 02115; e-mail: mcudkowicz{at}partners.org

Objective: Transgenic mice that overexpress a human gene encoding mutant cytosolic superoxide dismutase (SOD1) develop a progressive motor neuron loss that resembles human ALS. Why mutant SOD1 initiates motor neuron death is unknown. One hypothesis proposes that the mutant molecule has enhanced peroxidase activity, reducing hydrogen peroxide (H2O2) to form toxic hydroxyl adducts on critical targets. To test this hypothesis, the authors generated transgenic ALS mice with altered levels of glutathione peroxidase (GSHPx), the major soluble enzyme that detoxifies H2O2.

Methods: SOD1G93A ALS mice were bred with mice bearing a murine GSHPx transgene that have a four-fold elevation in brain GSHPx levels and with mice having targeted inactivation of the GSHPx gene and reduced brain GSHPx activity.

Results: Survival was not prolonged in ALS mice with elevated brain GSHPx activity (p = 0.09). ALS mice with decreased GSHPx brain activity (20% of normal) showed no acceleration of the disease course (p = 0.89). The age at disease onset in the ALS mice was unaffected by brain GSHPx activity.

Conclusion: The level of GSHPx activity in the CNS of transgenic ALS mice does not play a critical role in the development of motor neuron disease.




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B. J. Traynor, L. Bruijn, R. Conwit, F. Beal, G. O'Neill, S. C. Fagan, and M. E. Cudkowicz
Neuroprotective agents for clinical trials in ALS: A systematic assessment.
Neurology, July 11, 2006; 67(1): 20 - 27.
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