title: Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.
abstract: Abstract Dorfin is a RING-finger type ubiquitin ligase for mutant superoxide dismutase 1 (SOD1) that enhances its degradation. Mutant SOD1s cause familial amyotrophic lateral sclerosis (FALS) through the gain of unelucidated toxic properties. We previously showed that the accumulation of mutant SOD1 in the mitochondria triggered the release of cytochrome c, followed by the activation of the caspase cascade and induction of neuronal cell death. In the present study, therefore, we investigated whether Dorfin can modulate the level of mutant SOD1 in the mitochondria and subsequent caspase activation. We showed that Dorfin significantly reduced the amount of mutant SOD1 in the mitochondria, the release of cytochrome c and the activation of the following caspase cascade, thereby preventing eventual neuronal cell death in a neuronal cell model of FALS. These results suggest that reducing the accumulation of mutant SOD1 in the mitochondria may be a new therapeutic strategy for mutant SOD1-associated FALS, and that Dorfin may play a significant role in this.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Niwa
authors.forename: Nozomi
authors.initials: N
authors.lastname: Hishikawa
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Manabu
authors.initials: M
authors.lastname: Doyu
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; C000606290:SOD1 protein, human; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; C109415:SOD1 G93A protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C423571:RNF19A protein, human; D044767:Ubiquitin-Protein Ligases; D020169:Caspases