Abstract
ALS is a devastating neurodegenerative disorder for which no effective treatment exists. The precise molecular mechanisms underlying the selective degeneration of motor neurons are still unknown. A motor neuron specific apoptotic pathway involving Fas and NO has been discovered. Motor neurons from ALS-mice have an increased sensitivity to Fas-induced cell death via this pathway. In this study we therefore crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice to investigate whether the reduced Fas signaling could have beneficial effects on motor neuron death. G93A-SOD1 mutant mice with a homozygous FasL mutant showed a modest but statistically significant extension of survival, and reduced loss of motor neurons. These results indicate that motor neuron apoptosis triggered by Fas is relevant in ALS pathogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Amyotrophic Lateral Sclerosis / genetics*
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Amyotrophic Lateral Sclerosis / mortality
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Amyotrophic Lateral Sclerosis / physiopathology*
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Animals
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Behavior, Animal
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Cell Count / methods
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Disease Models, Animal
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Fas Ligand Protein / metabolism*
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Fas Ligand Protein / physiology
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Immunohistochemistry / methods
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Activity / physiology
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Motor Neurons / metabolism
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Nitric Oxide Synthase Type I / metabolism
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Probability
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Spinal Cord / pathology
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Superoxide Dismutase / genetics*
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Superoxide Dismutase / metabolism
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Survival Analysis
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism
Substances
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Fas Ligand Protein
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3-nitrotyrosine
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Tyrosine
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Nitric Oxide Synthase Type I
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SOD1 G93A protein
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Superoxide Dismutase