title: Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation.
abstract: Unfolded protein responses, including induction of stress sensor kinases, chaperones, and apoptotic mediators, are involved in the familial amyotrophic lateral sclerosis (ALS) model related to mutant Cu/Zn superoxide dismutase (SOD1) and sporadic ALS. We hypothesized that the endoplasmic reticulum-resident factor Derlin-1 plays a pivotal role in the regulation of misfolded proteins evoked by mutant SOD1. We show that Derlin-1 overexpression reduced mutant SOD1-induced cell toxicity and increased cell viability by suppressing the activation of the ER stress pathway factors: immunoglobulin-binding protein, activating transcription factor 6 p50, and C/EBP homologous protein. Interestingly, exogenous Derlin-1 resulted in a decrease in the amount of mutant SOD1, and a lesser decrease in that of wild-type SOD1, in transfected cells. Reduced SOD1 protein expression was observed in the microsomal fraction of wild-type and mutant SOD1 cells. Our results indicate that Derlin-1 regulates the turn over of SOD1 by promoting the proteasomal and autophagosomal degradation of SOD1 protein, but not by decreasing mutant SOD1 mRNA levels. Insights into the effects of Derlin-1 on mutant SOD1 may facilitate advancements in the treatment of motor neuron degeneration associated with ALS.
authors.affiliation: Department of Neurology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mori
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Uchino
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Suga
authors.forename: Tokunori
authors.initials: T
authors.lastname: Ikeda
authors.forename: Koutaro
authors.initials: K
authors.lastname: Takamatsu
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ishizaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Koide
authors.forename: En
authors.initials: E
authors.lastname: Kimura
authors.forename: Shuji
authors.initials: S
authors.lastname: Mita
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Maeda
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Hirano
authors.forename: Makoto
authors.initials: M
authors.lastname: Uchino
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D013312:Stress, Physiological / Q000235:genetics*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; C000606290:SOD1 protein, human; C530424:derlin-1 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D046988:Proteasome Endopeptidase Complex