Impaired slow axonal transport in wobbler mouse motor neuron disease


  • Dr Hiroshi Mitsumoto MD,

    Corresponding author
    1. Neuromuscular Disease Program, Department of Neurology, Cleveland Clinic Foundation, Case Western Reserve University, Cleveland, OH
    • Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH 44106
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  • Pierluigi Gambetti MD

    1. Division of Neuropathology (Pathology), Institute of Pathology, Case Western Reserve University, Cleveland, OH
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We studied slow axonal transport and morphometry of forelimb axons in wobbler mice and controls. In wobbler mice, the total radioactivity migrating with the slow transport was decreased by 50%. The velocity of transport also appeared to be reduced; 15 days following administration of a radioisotope, polypeptides migrating with slow component a of transport did not form a peak and remained mostly 2 mm from the spinal cord, while in controls slow component a was distributed as a peak which was located 4 mm from the cord. The ratios of the 68-kDa neurofilament subunit to tubulin and actin were significantly decreased (p < 0.01 and p < 0.005, respectively). This finding is consistent with a preferential reduction of the radioactivity migrating with neurofilament proteins in wobbler mice. Moreover, both the size and number of myelinated axons were markedly diminished, but their length was not significantly different, indicating that dying-back does not take place in axons of wobbler mice up to 12 mm from the spinal cord. The reduction in axonal transport may be due to the reduction in number and caliber of the axons and/or to reduced protein synthesis in cervical lower motor neurons; however, the abnormal distribution of the radioactive substance definitely results from impairment of the slow transport in the axons of the forelimb roots of wobbler mice. The transport impairment is not related to the presence of morphological changes in the perikaryon of wobbler mouse lower motor neurons, as it is much more widespread than would be expected if only altered neurons were involved. Whether the impairment of the slow transport is the primary pathogenetic event in wobbler mouse lower motor neuron disease, as well as in other animals and human motor neuron diseases, remains to be established.