title: Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice.
abstract: Glaucoma is one of the leading causes of bilateral blindness affecting nearly 8 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) and is often associated with elevated intraocular pressure (IOP). However, patients with normal tension glaucoma (NTG), a subtype of primary open-angle glaucoma (POAG), develop the disease without IOP elevation. The molecular pathways leading to the pathology of NTG and POAG are still unclear. Here, we describe the phenotypic characteristics of transgenic mice overexpressing wild-type (Wt) or mutated optineurin (Optn). Mutations E50K, H486R and Optn with a deletion of the first (amino acids 153-174) or second (amino acids 426-461) leucine zipper were used for overexpression. After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP. E50K mice also showed massive apoptosis and degeneration of entire retina, leading to approximately a 28% reduction of the retina thickness. At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane. Wt Optn and an active GTP-bound form of Rab8 complex were localized at the Golgi complex. These data suggest that alternation of the Optn sequence can initiate significant retinal degeneration in mice.
authors.affiliation: National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
authors.forename: Zai-Long
authors.initials: ZL
authors.lastname: Chi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Akahori
authors.forename: Minoru
authors.initials: M
authors.lastname: Obazawa
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Minami
authors.forename: Toru
authors.initials: T
authors.lastname: Noda
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakaya
authors.forename: Stanislav
authors.initials: S
authors.lastname: Tomarev
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Kawase
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Setsuko
authors.initials: S
authors.lastname: Noda
authors.forename: Masaki
authors.initials: M
authors.lastname: Sasaoka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimazaki
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Takada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwata
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism*; D005901:Glaucoma / Q000235:genetics*; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009900:Optic Nerve / Q000473:pathology; D011485:Protein Binding; D012162:Retinal Degeneration / Q000235:genetics*; D012165:Retinal Ganglion Cells / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D005136:Eye Proteins; D026901:Membrane Transport Proteins; D050505:Mutant Proteins; C501288:Optn protein, mouse; C521976:Rab8 protein, mouse; D020691:rab GTP-Binding Proteins
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