Abstract
Disruptions in axonal transport have been implicated in a wide range of neurodegenerative diseases. Cramping 1 (Cra1/+) and Legs at odd angles (Loa/+) mice, with hypomorphic mutations in the dynein heavy chain 1 gene, which encodes the ATPase of the retrograde motor protein dynein, were originally reported to exhibit late onset motor neuron disease. Subsequent, conflicting reports suggested that sensory neuron disease without motor neuron loss underlies the phenotypes of Cra1/+ and Loa/+ mice. Here, we present behavioral and anatomical analyses of Cra1/+ mice. We demonstrate that Cra1/+ mice exhibit early onset, stable behavioral deficits, including abnormal hindlimb posturing and decreased grip strength. These deficits do not progress through 24 months of age. No significant loss of primary motor neurons or dorsal root ganglia sensory neurons was observed at ages where the mice exhibited clear symptomatology. Instead, there is a decrease in complexity of neuromuscular junctions. These results indicate that disruption of dynein function in Cra1/+ mice results in abnormal morphology of neuromuscular junctions. The time course of behavioral deficits, as well as the nature of the morphological defects in neuromuscular junctions, suggests that disruption of dynein function in Cra1/+ mice causes a developmental defect in synapse assembly or stabilization.
Highlights
Rapid axonal transport is essential for neurons with long axons, both for development and mature functioning
Analysis of muscle fibers provides evidence of continuous muscle degeneration and regeneration. These results suggest that the primary pathology in Cra1/+ animals may be an early onset, non-progressive synaptic dysfunction that affects the neuromuscular junction
Previous reports on mice with hypomorphic mutations in dynein, the Cra1/+, Loa/+ or Swl/+ mice, described a late-onset degeneration of motor neurons, with progressive decline in motor neuron function and number [9], or an early-onset degeneration of proprioceptive sensory neurons
Summary
Rapid axonal transport is essential for neurons with long axons, both for development and mature functioning. Because of the importance of axonal transport, it is not surprising that disruptions in this process have been implicated in a wide range of neurodegenerative diseases, including motor and sensory neuropathies, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease [1,2,3,4]. Perhaps because of the long distance between cell bodies and distal axons in these neurons (over 1 meter in an adult human), sensory and motor neurons appear to be sensitive to disruptions in axonal transport. Disruptions in retrograde transport have been implicated in neurodegenerative disease in mice as well as in humans. A mutation in the p150Glued subunit of the dynactin complex has been discovered in a family with a progressive autosomal dominant form of lower motor neuron disease, and mice with mutations in p150Glued develop motor neuron disease [7,8,6]
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