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Experimental transmissibility of mutant SOD1 motor neuron disease

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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.

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Acknowledgments

We thank Drs. Todd Golde and Benoit Giasson for helpful advice over the course of these experiments. This work was supported by a Grant from the Packard Center for ALS Research at John’s Hopkins University and the Milton Safenowitz Post-Doctoral Fellowship for ALS Research awarded by the ALS Association. The authors declare they have no competing interests.

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Authors and Affiliations

  1. Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Box 100159, Gainesville, FL, 32610, USA

    Jacob I. Ayers, Susan Fromholt, Morgan Koch, Adam DeBosier, Ben McMahon, Guilian Xu & David R. Borchelt

  2. SantaFe HealthCare Alzheimer’s Disease Research Center, McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA

    Guilian Xu & David R. Borchelt

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  1. Jacob I. Ayers
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  2. Susan Fromholt
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  3. Morgan Koch
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  7. David R. Borchelt
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Correspondence to Jacob I. Ayers or David R. Borchelt.

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Ayers, J.I., Fromholt, S., Koch, M. et al. Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathol 128, 791–803 (2014). https://doi.org/10.1007/s00401-014-1342-7

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  • DOI: https://doi.org/10.1007/s00401-014-1342-7

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