title: Genetic background effects on disease onset and lifespan of the mutant dynactin p150Glued mouse model of motor neuron disease.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons in the central nervous system. Although most cases of ALS are sporadic, about 5-10% of cases are familial (FALS) with approximately 20% of FALS caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. We have reported that hSOD1-G93A transgenic mice modeling this disease show a more severe phenotype when the transgene is bred on a pure SJL background and a milder phenotype when bred on a pure B6 background and that these phenotype differences link to a region on mouse Chromosome 17.To examine whether other models of motor neuron degeneration are affected by genetic background, we bred the mutant human dynactin p150Glued (G59S-hDCTN1) transgene onto inbred SJL and B6 congenic lines. This model is based on an autosomal dominant lower motor neuron disease in humans linked to a mutation in the p150Glued subunit of the dynactin complex. As seen in hSOD1-G93A mice, we observed a more severe phenotype with earlier disease onset (p<0.001) and decreased survival (p<0.00001) when the G59S-hDCTN1 transgene was bred onto the SJL background and delayed onset (p<0.0001) with increased survival (p<0.00001) when bred onto the B6 background. Furthermore, B6 mice with an SJL derived chromosome 17 interval previously shown to delay disease onset in hSOD1-G93A mice also showed delays onset in G59S-hDCTN1 mice suggesting that at least some genetic modifiers are shared. We have shown that genetic background influences phenotype in G59S-hDCTN1 mice, in part through a region of chromosome 17 similar to the G93-hSOD1 ALS mouse model. These results support the presence of genetic modifiers in both these models some of which may be shared. Identification of these modifiers will highlight intracellular pathways involved in motor neuron disease and provide new therapeutic targets that may be applicable to motor neuron degeneration.
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
authors.affiliation: Department of Microbiology Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Blankenhorn
authors.affiliation: Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, United States of America.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Sher
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Juliann
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Welsh
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Meredith C
authors.initials: MC
authors.lastname: Dixon
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Jeffrey
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
authors.affiliation: The Jackson Laboratory, Bar Harbour, Maine, United States of America.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
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
mesh_terms: D000818:Animals; D001947:Breeding / Q000379:methods*; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004195:Disease Models, Animal; D000072159:Dynactin Complex; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1