Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice
| Autor: | Toru Noda, Atsushi Shimazaki, Setsuko Noda, Masaki Sasaoka, Takeshi Iwata, Masayoshi Minami, Yuichiro Takada, Stanislav I. Tomarev, Tetsuya Yamamoto, Masakazu Akahori, Zai-Long Chi, Naoki Nakaya, Kazuhide Kawase, Minoru Obazawa |
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| Rok vydání: | 2010 |
| Předmět: |
Retinal Ganglion Cells
Retinal degeneration genetic structures Nerve fiber layer Glaucoma Apoptosis Cell Cycle Proteins Mice Inbred Strains Mice Transgenic Biology Retinal ganglion Mice Normal tension glaucoma Genetics medicine Animals Eye Proteins Molecular Biology Genetics (clinical) Optineurin Retina Retinal Degeneration Membrane Transport Proteins Optic Nerve Articles General Medicine medicine.disease eye diseases Cell biology medicine.anatomical_structure Amino Acid Substitution rab GTP-Binding Proteins Optic nerve Mutant Proteins sense organs Protein Binding |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddq146 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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