Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons.
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.
Williamson
T L
TL
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla 92093, USA.
Cleveland
D W
DW
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D009154:Mutation / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013997:Time Factors
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1