title: A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in the death of motor neurons in the brain and spinal cord. The disorder generally strikes in mid-life, relentlessly leading to paralysis and death, typically 3-5 years after diagnosis. No effective treatments are available. Up to 10% of ALS is familial, usually autosomal dominant. Several causative genes are known and, of these, mutant superoxide dismutase 1 (SOD1) is by far the most frequently found, accounting for up to 20% of familial ALS. A range of human mutant SOD1 transgenic mouse strains has been produced, and these largely successfully model the human disease. Of these, the most widely used is the SOD1 mouse, which expresses a human SOD1 transgene with a causative G93A mutation. This mouse model is excellent for many purposes but carries up to 25 copies of the transgene and produces a great excess of SOD1 protein, which might affect our interpretation of disease processes. A variant of this strain carries a deletion of the transgene array such that the copy number is dropped to eight to ten mutant SOD1 genes. This 'deleted' 'low-copy' mouse undergoes a slower course of disease, over many months. Here we have carried out a comprehensive analysis of phenotype, including nerve and muscle physiology and histology, to add to our knowledge of this 'deleted' strain and give baseline data for future studies. We find differences in phenotype that arise from genetic background and sex, and we quantify the loss of nerve and muscle function over time. The slowly progressive pathology observed in this mouse strain could provide us with a more appropriate model for studying early-stage pathological processes in ALS and aid the development of therapies for early-stage treatments.
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK.
authors.forename: Abraham
authors.initials: A
authors.lastname: Acevedo-Arozena
authors.forename: Bernadett
authors.initials: B
authors.lastname: Kalmar
authors.forename: Shafa
authors.initials: S
authors.lastname: Essa
authors.forename: Thomas
authors.initials: T
authors.lastname: Ricketts
authors.forename: Peter
authors.initials: P
authors.lastname: Joyce
authors.forename: Rosie
authors.initials: R
authors.lastname: Kent
authors.forename: Claire
authors.initials: C
authors.lastname: Rowe
authors.forename: Andy
authors.initials: A
authors.lastname: Parker
authors.forename: Anna
authors.initials: A
authors.lastname: Gray
authors.forename: Majid
authors.initials: M
authors.lastname: Hafezparast
authors.forename: Julian R
authors.initials: JR
authors.lastname: Thorpe
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D023381:Endpoint Determination; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D005911:Gliosis / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D018737:Hand Strength / Q000502:physiology; D006614:Hindlimb / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D009132:Muscles / Q000473:pathology / Q000503:physiopathology; D017510:Protein Folding; D013216:Reflex, Startle / Q000502:physiology; D045442:Rotarod Performance Test; D012727:Sex Characteristics; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1