Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity.
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
SOD1(G93A) 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.


CONCLUSIONS
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.
Cudkowicz
M E
ME
Day Neuromuscular Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. mcudkowicz@partners.org
Pastusza
K A
KA
Sapp
P C
PC
Mathews
R K
RK
Leahy
J
J
Pasinelli
P
P
Francis
J W
JW
Jiang
D
D
Andersen
J K
JK
Brown
R H
RH
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D001921:Brain / Q000201:enzymology*; D005260:Female; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis
C000606290:SOD1 protein, human; D005979:Glutathione Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1