title: Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.
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.
authors.affiliation: Neuroapoptosis Laboratory and Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: V O
authors.initials: VO
authors.lastname: Ona
authors.forename: C
authors.initials: C
authors.lastname: Guégan
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: V
authors.initials: V
authors.lastname: Jackson-Lewis
authors.forename: L J
authors.initials: LJ
authors.lastname: Andrews
authors.forename: A J
authors.initials: AJ
authors.lastname: Olszewski
authors.forename: P E
authors.initials: PE
authors.lastname: Stieg
authors.forename: J P
authors.initials: JP
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Przedborski
authors.forename: R M
authors.initials: RM
authors.lastname: Friedlander
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009410:Nerve Degeneration; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011597:Psychomotor Performance; D013116:Spinal Cord / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D018696:Neuroprotective Agents; C000606290:SOD1 protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1