title: Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity.
abstract: 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.
authors.affiliation: Day Neuromuscular Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. mcudkowicz@partners.org
authors.forename: M E
authors.initials: ME
authors.lastname: Cudkowicz
authors.forename: K A
authors.initials: KA
authors.lastname: Pastusza
authors.forename: P C
authors.initials: PC
authors.lastname: Sapp
authors.forename: R K
authors.initials: RK
authors.lastname: Mathews
authors.forename: J
authors.initials: J
authors.lastname: Leahy
authors.forename: P
authors.initials: P
authors.lastname: Pasinelli
authors.forename: J W
authors.initials: JW
authors.lastname: Francis
authors.forename: D
authors.initials: D
authors.lastname: Jiang
authors.forename: J K
authors.initials: JK
authors.lastname: Andersen
authors.forename: R H
authors.initials: RH
authors.lastname: Brown
mesh_terms: 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
chemical_list: C000606290:SOD1 protein, human; D005979:Glutathione Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1