title: Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase.
abstract: The mechanism by which mutations in the superoxide dismutase (SOD1) gene cause motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS) is unknown. Recent reports that neuronal death in SOD1-familial ALS is apoptotic have not documented activation of cell death genes. We present evidence that the enzyme caspase-1 is activated in neurons expressing mutant SOD1 protein. Proteolytic processing characteristic of caspase-1 activation is seen both in spinal cords of transgenic ALS mice and neurally differentiated neuroblastoma (line N2a) cells with SOD1 mutations. This activation of caspase-1 is enhanced by oxidative challenge (xanthine/xanthine oxidase), which triggers cleavage and secretion of the interleukin 1beta converting enzyme substrate, pro-interleukin 1beta, and induces apoptosis. This N2a culture system should be an instructive in vitro model for further investigation of the proapoptotic properties of mutant SOD1.
authors.affiliation: Massachusetts General Hospital-East, Charlestown, MA 02129, USA.
authors.forename: P
authors.initials: P
authors.lastname: Pasinelli
authors.forename: D R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: M K
authors.initials: MK
authors.lastname: Houseweart
authors.forename: D W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: R H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D051379:Mice; D016296:Mutagenesis; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D011994:Recombinant Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D007375:Interleukin-1; D011994:Recombinant Proteins; D013482:Superoxide Dismutase; D020170:Caspase 1