Abstract
Selective degeneration and death of motor neurons in SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS) is accompanied by axonal disorganization and reduced slow axonal transport in the three most frequently used mouse models of mutant SOD1-mediated ALS. To test whether suppression of axonal degeneration (frequently known as Wallerian degeneration) could slow disease development, we took advantage of a spontaneous mouse mutant Wld(s) (Wallerian degeneration slow) in which the programmed axonal degenerative process that is normally activated after axonal injury is significantly delayed. Despite its effectiveness in delaying axonal loss in other neurodegenerative models, the presence of Wld(s) did not slow disease onset, ameliorate mutant motor neuron death, axonal degeneration, or preserve synaptic attachments in mice that develop disease from ALS-linked SOD1 mutants SOD1G37R or SOD1G85R. However, presynaptic endings in both the presence and absence of Wld(s) showed high accumulations of mitochondria and synaptic vesicles, implicating errors of retrograde transport as a consequence of SOD1-mutant damage to axons.
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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Animals
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Axonal Transport / genetics
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Cytoprotection / genetics*
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Disease Models, Animal
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Humans
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Mice
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Mice, Mutant Strains
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Mice, Transgenic
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Microscopy, Electron, Transmission
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Mitochondria / pathology
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Mitochondria / ultrastructure
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Motor Neuron Disease / enzymology
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Motor Neuron Disease / genetics*
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Motor Neuron Disease / physiopathology
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Motor Neurons / enzymology
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Motor Neurons / pathology
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Motor Neurons / ultrastructure
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Nerve Tissue Proteins / genetics*
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Neuromuscular Junction / pathology
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Neuromuscular Junction / ultrastructure
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Presynaptic Terminals / pathology
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Presynaptic Terminals / ultrastructure
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Spinal Cord / enzymology
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Spinal Cord / pathology
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Spinal Cord / ultrastructure
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Superoxide Dismutase / genetics*
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Superoxide Dismutase-1
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Synaptic Vesicles / pathology
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Synaptic Vesicles / ultrastructure
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Wallerian Degeneration / enzymology
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Wallerian Degeneration / genetics*
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Wallerian Degeneration / pathology
Substances
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Nerve Tissue Proteins
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SOD1 protein, human
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Wld protein, mouse
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1