Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice

• Published in: Human molecular genetics Vol. 19; no. 13; pp. 2606 - 2615
• Main Authors: Chi, Zai-Long, Akahori, Masakazu, Obazawa, Minoru, Minami, Masayoshi, Noda, Toru, Nakaya, Naoki, Tomarev, Stanislav, Kawase, Kazuhide, Yamamoto, Tetsuya, Noda, Setsuko, Sasaoka, Masaki, Shimazaki, Atsushi, Takada, Yuichiro, Iwata, Takeshi
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2010
• Subjects: Amino Acid Substitution; Animals; Apoptosis; Biological and medical sciences; Eye Proteins - genetics; Eye Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Glaucoma - genetics; Medical sciences; Mice; Mice, Inbred Strains; Mice, Transgenic; Molecular and cellular biology; Mutant Proteins - genetics; Mutant Proteins - metabolism; Ophthalmology; Optic Nerve - pathology; Protein Binding; rab GTP-Binding Proteins - metabolism; Retinal Degeneration - genetics; Retinal Ganglion Cells - pathology; Retinopathies; Macular degeneration; Progressive; Eye disease; Vertebrata; Mammalia; Retinopathy; Mouse; Rodentia; Gene overexpression; Genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq146

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.