title: Familial amyotrophic lateral sclerosis (FALS)-linked SOD1 mutation accelerates neuronal cell death by activating cleavage of caspase-4 under ER stress in an in vitro model of FALS.
abstract: Recently, endoplasmic reticulum (ER) dysfunction has been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (FALS). Although up-regulation of caspase-12 has been reported in G93A SOD1 transgenic mice, it is controversial whether similar mechanisms operate in human FALS. We found that ER stress in cells stably expressing L84V SOD1 induces neuronal cell death and accelerates cleavage of caspase-4. We also detected oligomer formation of L84V SOD1 in L84V SOD1-expressing human neuroblastoma cells. These findings show that ER stress in L84V SOD1-expressing human cells causes the aggregation and inclusion bodies of L84V SOD1 to induce neuronal death through the accelerated cleavage of caspase-4.
authors.affiliation: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Koyama
authors.forename: Toru
authors.initials: T
authors.lastname: Hiratsuka
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Matsuzaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kato
authors.forename: Taiichi
authors.initials: T
authors.lastname: Katayama
authors.forename: Masaya
authors.initials: M
authors.lastname: Tohyama
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D053471:Caspases, Initiator / Q000378:metabolism*; D002449:Cell Aggregation / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C093516:CASP4 protein, human; D053471:Caspases, Initiator