title: Optineurin suppression causes neuronal cell death via NF-κB pathway.
abstract: Mutations in more than 10 genes are reported to cause familial amyotrophic lateral sclerosis (ALS). Among these genes, optineurin (OPTN) is virtually the only gene that is considered to cause classical ALS by a loss-of-function mutation. Wild-type optineurin (OPTN(WT) ) suppresses nuclear factor-kappa B (NF-κB) activity, but the ALS-causing mutant OPTN is unable to suppress NF-κB activity. Therefore, we knocked down OPTN in neuronal cells and examined the resulting NF-κB activity and phenotype. First, we confirmed the loss of the endogenous OPTN expression after siRNA treatment and found that NF-κB activity was increased in OPTN-knockdown cells. Next, we found that OPTN knockdown caused neuronal cell death. Then, overexpression of OPTN(WT) or OPTN(E) (50K) with intact NF-κB-suppressive activity, but not overexpression of ALS-related OPTN mutants, suppressed the neuronal death induced by OPTN knockdown. This neuronal cell death was inhibited by withaferin A, which selectively inhibits NF-κB activation. Lastly, involvement of the mitochondrial proapoptotic pathway was suggested for neuronal death induced by OPTN knockdown. Taken together, these results indicate that inappropriate NF-κB activation is the pathogenic mechanism underlying OPTN mutation-related ALS. Among the genes for typical amyotrophic lateral sclerosis (ALS) phenotypes, optineurin (OPTN) is virtually the only gene in which a loss-of-function mutation is considered as the principal disease mechanism. We found that OPTN knockdown induced neuronal cell death via NF-κB activation. Furthermore, proapoptotic molecules such as p53 and Bax representing downstream targets of NF-κB are suggested to be involved in neuronal death.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Akizuki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamashita
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D002452:Cell Count; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D004396:Coloring Agents; D005136:Eye Proteins / Q000235:genetics*; D017930:Genes, Reporter; D016158:Genes, p53 / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D009154:Mutation / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014343:Trypan Blue; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D054358:Withanolides / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D005136:Eye Proteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C501288:Optn protein, mouse; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D054358:Withanolides; D008156:Luciferases; D014343:Trypan Blue; C009684:withaferin A
keywords: NF-κB; amyotrophic lateral sclerosis; optineurin