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.
