Abstract
To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. Mice overexpressing dynamitin demonstrate a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle. Previous transgenic mouse models of ALS have shown abnormalities in microtubule-based axonal transport. In this report, we describe a mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyotrophic Lateral Sclerosis / genetics*
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Amyotrophic Lateral Sclerosis / metabolism*
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Amyotrophic Lateral Sclerosis / physiopathology
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Animals
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Axonal Transport / genetics*
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Axons / metabolism*
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Axons / pathology
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Axons / ultrastructure
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Cell Death / genetics
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Disease Models, Animal
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Dynactin Complex
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Dyneins / deficiency*
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Dyneins / genetics
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Female
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Male
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Mice
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Mice, Transgenic
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Microscopy, Electron
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Microtubule-Associated Proteins / deficiency*
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Motor Neurons / metabolism*
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Motor Neurons / pathology
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Motor Neurons / ultrastructure
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Muscular Atrophy / genetics
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Muscular Atrophy / metabolism
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Muscular Atrophy / physiopathology
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Neurofilament Proteins / genetics
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Neurofilament Proteins / metabolism
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Phenotype
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Spinal Cord / metabolism*
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Spinal Cord / pathology
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Spinal Cord / physiopathology
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Spinal Nerve Roots / metabolism
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Spinal Nerve Roots / pathology
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Spinal Nerve Roots / ultrastructure
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Up-Regulation / genetics
Substances
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Dctn2 protein, mouse
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Dynactin Complex
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Microtubule-Associated Proteins
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Neurofilament Proteins
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Dyneins