Mutant superoxide dismutase disrupts cytoplasmic dynein in motor neurons.

Cytoplasmic dynein and dynactin drive retrograde axonal transport in neurons, and mutations in dynein/dynactin cause motor neuron degeneration. To test whether defects in dynein/dynactin function are involved in the neurodegenerative disease amyotrophic lateral sclerosis, we examined neurotracer transport from muscle to motor neuron in a transgenic mouse model of amyotrophic lateral sclerosis. Significant inhibition was observed, which was temporally correlated with declines in muscle strength. No decrease in dynein/dynactin expression was observed, but immunohistochemistry suggests that dynein associates with aggregates of mutant Cu/Zn superoxide dismutase 1. Expression of mutant Cu/Zn superoxide dismutase 1 in primary motor neurons altered the cellular localization of dynein, suggesting an inhibition of dynein/dynactin function. Thus, inhibition of dynein/dynactin function may have a role in motor neuron degeneration in amyotrophic lateral sclerosis.