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Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways

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Abstract

A hallmark feature of amyotrophic lateral sclerosis (ALS) is that symptoms appear to spread along neuroanatomical pathways to engulf the motor nervous system, suggesting a propagative toxic entity could be involved in disease pathogenesis. Evidence for such a propagative entity emerged recently in studies using mice that express G85R-SOD1 mutant protein fused to YFP (G85R-SOD1:YFP). Heterozygous G85R-SOD1:YFP transgenic mice do not develop ALS symptoms out to 20 months of age. However, when newborns are injected with spinal homogenates from paralyzed mutant SOD1 mice, the G85R-SOD1:YFP mice develop paralysis as early as 6 months of age. We now demonstrate that injecting spinal homogenates from paralyzed mutant SOD1 mice into the sciatic nerves of adult G85R-SOD1:YFP mice produces a spreading motor neuron disease within 3.0 ± 0.2 months of injection. The formation of G85R-SOD1:YFP inclusion pathology spreads slowly in this model system; first appearing in the ipsilateral DRG, then lumbar spinal cord, before spreading rostrally up to the cervical cord by the time mice develop paralysis. Reactive astrogliosis mirrors the spread of inclusion pathology and motor neuron loss is most severe in lumbar cord. G85R-SOD1:YFP inclusion pathology quickly spreads to discrete neurons in the brainstem and midbrain that are synaptically connected to spinal neurons, suggesting a trans-synaptic propagation of misfolded protein. Taken together, the data presented here describe the first animal model that recapitulates the spreading phenotype observed in patients with ALS, and implicates the propagation of misfolded protein as a potential mechanism for the spreading of motor neuron disease.

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Acknowledgments

We thank Drs. Todd Golde, Benoit Giasson, and Anthony Kincaid for helpful advice over the course of these experiments. This work was supported by a grant from the National Institutes of Neurological Disease and Stoke (1R01NS092788-01), the Packard Center for ALS Research at Johns Hopkins University and the Milton Safenowitz Post-Doctoral Fellowship for ALS Research awarded by the ALS Association.

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Authors and Affiliations

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

    Jacob I. Ayers, Susan E. Fromholt, Veronica M. O’Neal, Jeffrey H. Diamond & David R. Borchelt

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

    David R. Borchelt

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  1. Jacob I. Ayers
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  2. Susan E. Fromholt
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Correspondence to Jacob I. Ayers.

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Ayers, J.I., Fromholt, S.E., O’Neal, V.M. et al. Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways. Acta Neuropathol 131, 103–114 (2016). https://doi.org/10.1007/s00401-015-1514-0

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