title: Effects of optineurin mutants on SH-SY5Y cell survival.
abstract: Mutations in the optineurin gene (OPTN) have been found to be associated with glaucoma and amyotrophic lateral sclerosis (ALS). However, the mechanism by which this single gene mutation leads to neurodegeneration in those two diseases remains unrevealed. To study the roles of wild-type (WT) OPTN and its pathogenic mutants in neuronal survival, here we overexpressed SH-SY5Y cells with WT OPTN or its four mutants (E50K, M98K, Q398X and E478G), and detected their effects on neuronal viability under normal or oxidative stress conditions. We found that overexpression of WT OPTN or its glaucoma-linked mutants (E50K and M98K) causes little harm in SH-SY5Y cells, while ALS-associated OPTN mutants (Q398X and E478G) leads to remarkably increased oxidative status and decreased antioxidase activity, which might result in severe mitochondrial dysfunction and neuronal injury. Further investigation suggests that overexpression of WT OPTN promotes endogenous antioxidase activation in the SH-SY5Y cells under oxidative stress and increases neuronal survival. Nevertheless, this neuroprotective effect of WT OPTN is abolished by its four mutants. Our results indicate that oxidative stress may play a central role in the pathogenesis of glaucoma and ALS caused by OPTN mutation.
authors.affiliation: Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200032, China; Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Chongqing Medical University, China.
authors.forename: Ang
authors.initials: A
authors.lastname: Li
authors.affiliation: Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200032, China; Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai 200032, China.
authors.forename: Junyi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200032, China; Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai 200032, China. Electronic address: zsheent@gmail.com.
authors.forename: Shenghai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200032, China; Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai 200032, China. Electronic address: jihongwu@fudan.edu.cn.
authors.forename: Jihong
authors.initials: J
authors.lastname: Wu
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D006801:Humans; D026901:Membrane Transport Proteins; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism*; D035582:Transcription Factor TFIIIA / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA
keywords: Mutation; Neuronal survival; Optineurin; Oxidative stress