Abstract
Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G93A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A) mice, which suggests that caspase inhibition may have a protective role in ALS.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Chloromethyl Ketones / administration & dosage
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Amino Acid Chloromethyl Ketones / pharmacology*
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Amino Acid Chloromethyl Ketones / therapeutic use
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Amino Acid Substitution
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Amyotrophic Lateral Sclerosis / drug therapy*
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Amyotrophic Lateral Sclerosis / enzymology*
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Apoptosis / drug effects
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Caspase 1 / genetics
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Caspase 1 / metabolism*
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Caspase 3
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Caspase Inhibitors
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Caspases / genetics
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Caspases / metabolism*
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Cysteine Proteinase Inhibitors / administration & dosage
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Cysteine Proteinase Inhibitors / pharmacology
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Cysteine Proteinase Inhibitors / therapeutic use
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Disease Models, Animal
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Disease Progression
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Enzyme Activation
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Gene Expression Regulation, Enzymologic
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Humans
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Injections, Intraventricular
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Interleukin-1 / metabolism
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Male
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Mice
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Mice, Transgenic
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Motor Neurons / drug effects*
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Motor Neurons / enzymology
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Motor Neurons / pathology
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Nerve Degeneration
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Psychomotor Performance
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Spinal Cord / enzymology
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
Substances
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Amino Acid Chloromethyl Ketones
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Interleukin-1
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Neuroprotective Agents
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SOD1 protein, human
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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CASP3 protein, human
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Casp3 protein, mouse
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Caspase 3
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Caspases
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Caspase 1