title: Experimental transmissibility of mutant SOD1 motor neuron disease.
abstract: By unknown mechanisms, the symptoms of amyotrophic lateral sclerosis (ALS) seem to spread along neuroanatomical pathways to engulf the motor nervous system. The rate at which symptoms spread is one of the primary drivers of disease progression. One mechanism by which ALS symptoms could spread is by a prion-like propagation of a toxic misfolded protein from cell to cell along neuroanatomic pathways. Proteins that can transmit toxic conformations between cells often can also experimentally transmit disease between individual organisms. To survey the ease with which motor neuron disease (MND) can be transmitted, we injected spinal cord homogenates prepared from paralyzed mice expressing mutant superoxide dismutase 1 (SOD1-G93A and G37R) into the spinal cords of genetically vulnerable SOD1 transgenic mice. From the various models we tested, one emerged as showing high vulnerability. Tissue homogenates from paralyzed G93A mice induced MND in 6 of 10 mice expressing low levels of G85R-SOD1 fused to yellow fluorescent protein (G85R-YFP mice) by 3-11 months, and produced widespread spinal inclusion pathology. Importantly, second passage of homogenates from G93A → G85R-YFP mice back into newborn G85R-YFP mice induced disease in 4 of 4 mice by 3 months of age. Homogenates from paralyzed mice expressing the G37R variant were among those that transmitted poorly regardless of the strain of recipient transgenic animal injected, a finding suggestive of strain-like properties that manifest as differing abilities to transmit MND. Together, our data provide a working model for MND transmission to study the pathogenesis of ALS.
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA, jayers.123ja@ufl.edu.
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Ayers
authors.forename: Susan
authors.initials: S
authors.lastname: Fromholt
authors.forename: Morgan
authors.initials: M
authors.lastname: Koch
authors.forename: Adam
authors.initials: A
authors.lastname: DeBosier
authors.forename: Ben
authors.initials: B
authors.lastname: McMahon
authors.forename: Guilian
authors.initials: G
authors.lastname: Xu
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D016472:Motor Neuron Disease / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D010243:Paralysis / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1