title: Absence of p53: no effect in a transgenic mouse model of familial amyotrophic lateral sclerosis.
abstract: Familial amyotrophic lateral sclerosis (ALS) has been linked in some families to dominantly inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (Cu-Zn SOD1). Transgenic mice expressing a mutant human Cu-Zn SOD1 (G93A) develop a dominantly inherited adult-onset paralytic disorder that replicates many of the clinical and pathological features of familial ALS. Increased p53 immunoreactivity has been reported in the motor cortex and spinal ventral horns of postmortem tissue from ALS patients. The nuclear phosphoprotein p53 is an important regulator of cellular proliferation, and increasing evidence supports the role of p53 in regulating cellular apoptosis. To assess the role of p53-mediated apoptosis in amyotrophic lateral sclerosis, mice deficient in both p53 alleles (p53-/-) were crossed with transgenic mice expressing the G93A mutant (G93A+), creating novel transgenic knockout mice. The animals (p53 +/+G93A+, p53+/-G93A+, p53-/-G93A+) were examined at regular intervals for cage activity, upper and lower extremity strength, and mortality. At 120 days from birth mice from each genotype were sacrificed, and L2-L3 anterior horn motor neurons were counted. There was no significant difference in time to onset of behavioral decline, mortality, or motor neuron degeneration between the different genotypes. Despite evidence that p53 plays an important role after acute neuronal injury, the current study suggests that p53 is not significantly involved in cell death in the G93A+ transgenic mouse model of familial ALS.
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kuntz
authors.forename: Y
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
authors.forename: L A
authors.initials: LA
authors.lastname: Donehower
authors.forename: R S
authors.initials: RS
authors.lastname: Morrison
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002452:Cell Count; D005552:Forelimb / Q000503:physiopathology; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009043:Motor Activity; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000502:physiology
chemical_list: D016159:Tumor Suppressor Protein p53; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase