title: Phenotype of transgenic mice carrying a very low copy number of the mutant human G93A superoxide dismutase-1 gene associated with amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neuron. While most cases of ALS are sporadic, 10% are familial (FALS) with 20% of FALS caused by a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). There is variability in sporadic ALS as well as FALS where even within the same family some siblings with the same mutation do not manifest disease. A transgenic (Tg) mouse model of FALS containing 25 copies of the mutant human SOD1 gene demonstrates motor neuron pathology and progressive weakness similar to ALS patients, leading to death at approximately 130 days. The onset of symptoms and survival of these transgenic mice are directly related to the number of copies of the mutant gene. We report the phenotype of a very low expressing (VLE) G93A SOD1 Tg carrying only 4 copies of the mutant G93ASOD1 gene. While weakness can start at 9 months, only 74% of mice 18 months or older demonstrate disease. The VLE mice show decreased motor neurons compared to wild-type mice as well as increased cytoplasmic translocation of TDP-43. In contrast to the standard G93A SOD1 Tg mouse which always develops motor weakness leading to death, not all VLE animals manifested clinical disease or shortened life span. In fact, approximately 20% of mice older than 24 months had no motor symptoms and only 18% of VLE mice older than 22 months reached end stage. Given the variable penetrance of clinical phenotype, prolonged survival, and protracted loss of motor neurons the VLE mouse provides a new tool that closely mimics human ALS. This tool will allow the study of pathologic events over time as well as the study of genetic and environmental modifiers that may not be causative, but can exacerbate or accelerate motor neuron disease.
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Deitch
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Guillermo M
authors.initials: GM
authors.lastname: Alexander
authors.affiliation: Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bensinger
authors.affiliation: Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Juliann T
authors.initials: JT
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Heiman-Patterson
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D021381:Protein Transport; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis
chemical_list: D004268:DNA-Binding Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000606290:SOD1 protein, human; C578077:Tardbp protein, mouse; C000606291:Sod1 protein, mouse