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.
Ligon
Lee A
LA
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
LaMonte
Bernadette H
BH
Wallace
Karen E
KE
Weber
Nicholas
N
Kalb
Robert G
RG
Holzbaur
Erika L F
EL
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D020409:Molecular Motor Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D004398:Dyneins