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Slowing of axonal transport is a very early event in the toxicity of ALS–linked SOD1 mutants to motor neurons

Nature Neuroscience volume 2, pages 50–56 (1999)Cite this article

Abstract

Mutations in copper/zinc superoxide dismutase 1 (SOD1), primary causes of human amyotrophic lateral sclerosis (ALS), provoke motor neuron death through an unidentified toxic property. The known neurofilament–dependent slowing of axonal transport, combined with the prominent misaccumulation of neurofilaments in ALS, suggests that an important aspect of toxicity may arise from damage to transport. Here we verify this hypothesis for two SOD1 mutations linked to familial ALS. Reduced transport of selective cargoes of slow transport, especially tubulin, arises months before neurodegeneration. For one mutant, this represents the earliest detectable abnormality. Thus, damage to the cargoes or machinery of slow transport is an early feature of toxicity mediated by mutant SOD1.

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Figure 1: Retardation of slow axonal transport before disease onset in SOD1G37R mice.
Figure 2: Retardation of slow axonal transport seven months before disease onset in SOD1G37R mice.
Figure 3: Absence of motor neuron degeneration in SOD1G37R mice at four months of age and no detectable pathology in SOD1G85R mice at six months of age.
Figure 4: Retardation of slow axonal transport before pathological changes in SOD1G85R mice.
Figure 5: Accumulation of βIII–tubulin in the proximal axons of SOD1 mutant mice.
Figure 6: Distinct localization of βIII–tubulin, NF–H and SOD1.
Figure 7: Fast axonal transport remains unaffected in SOD1G37R mice.

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Acknowledgements

We acknowledge Karen L. Anderson, Janet S. Folmer and Scott D. Anderson for technical assistance. This work was supported by grant NS 27036 from the NIH and a grant from the Muscular Dystrophy Association to D.W.C. T.L.W. was supported, in part, by a postdoctoral fellowship from the Muscular Dystrophy Association. Salary support for D.W.C. is provided by the Ludwig Institute for Cancer Research.

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Toni L. Williamson & Don W. Cleveland

  2. Departments of Medicine and Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Don W. Cleveland

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Correspondence to Don W. Cleveland.

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Williamson, T., Cleveland, D. Slowing of axonal transport is a very early event in the toxicity of ALS–linked SOD1 mutants to motor neurons. Nat Neurosci 2, 50–56 (1999). https://doi.org/10.1038/4553

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