Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice
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...
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creator | 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 |
description | 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. |
doi_str_mv | 10.1093/hmg/ddq146 |
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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.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddq146</identifier><identifier>PMID: 20388642</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>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</subject><ispartof>Human molecular genetics, 2010-07, Vol.19 (13), p.2606-2615</ispartof><rights>2015 INIST-CNRS</rights><rights>The Author 2010. Published by Oxford University Press 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c543t-93519c91e1b6071e1704c186f82e166869ed39653073c0d884b2ff0fe71686823</citedby><cites>FETCH-LOGICAL-c543t-93519c91e1b6071e1704c186f82e166869ed39653073c0d884b2ff0fe71686823</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22883767$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20388642$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chi, Zai-Long</creatorcontrib><creatorcontrib>Akahori, Masakazu</creatorcontrib><creatorcontrib>Obazawa, Minoru</creatorcontrib><creatorcontrib>Minami, Masayoshi</creatorcontrib><creatorcontrib>Noda, Toru</creatorcontrib><creatorcontrib>Nakaya, Naoki</creatorcontrib><creatorcontrib>Tomarev, Stanislav</creatorcontrib><creatorcontrib>Kawase, Kazuhide</creatorcontrib><creatorcontrib>Yamamoto, Tetsuya</creatorcontrib><creatorcontrib>Noda, Setsuko</creatorcontrib><creatorcontrib>Sasaoka, Masaki</creatorcontrib><creatorcontrib>Shimazaki, Atsushi</creatorcontrib><creatorcontrib>Takada, Yuichiro</creatorcontrib><creatorcontrib>Iwata, Takeshi</creatorcontrib><title>Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>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.</description><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Eye Proteins - genetics</subject><subject>Eye Proteins - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Glaucoma - genetics</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Mice, Transgenic</subject><subject>Molecular and cellular biology</subject><subject>Mutant Proteins - genetics</subject><subject>Mutant Proteins - metabolism</subject><subject>Ophthalmology</subject><subject>Optic Nerve - pathology</subject><subject>Protein Binding</subject><subject>rab GTP-Binding Proteins - metabolism</subject><subject>Retinal Degeneration - genetics</subject><subject>Retinal Ganglion Cells - pathology</subject><subject>Retinopathies</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkdFqFDEUhoModq3e-ACSGykUxiaTTJK5EdpSXWmlpawo3oRs5sw2OpNMk5mlvr3Z7rrqTc7F_50vB36EXlPyjpKandz1q5OmuadcPEGz_JKiJIo9RTNSC16ImogD9CKlH4RQwZl8jg5KwpQSvJyhdL2GCA9DhJRc8Di0OAyj8zBF5_FFRS5x41KchjHhW7NU2PkRorHjBja-wR2YJuExYIOHGFaPnjXgCFliOtzACnxeeOSzsXcWXqJnrekSvNrNQ_Tlw8XifF5cXX_8dH56VdiKs7GoWUVrW1OgS0FkHpJwS5VoVQlUCCVqaFgtKkYks6RRii_LtiUtSJpDVbJD9H7rHaZlD40FP0bT6SG63sRfOhin_0-8u9OrsNalUoxxkgVHO0EM9xOkUfcuWeg64yFMSUsuSsZLQjN5vCVtDClFaPe_UKI3Jelckt6WlOE3_961R_-0koG3O8Aka7o2Gm9d-stt7pNCZq7Yci6N8LDPTfypcyorPf_2XS_OFpefv85v9Bn7DRYEq_Y</recordid><startdate>20100701</startdate><enddate>20100701</enddate><creator>Chi, Zai-Long</creator><creator>Akahori, Masakazu</creator><creator>Obazawa, Minoru</creator><creator>Minami, Masayoshi</creator><creator>Noda, Toru</creator><creator>Nakaya, Naoki</creator><creator>Tomarev, Stanislav</creator><creator>Kawase, Kazuhide</creator><creator>Yamamoto, Tetsuya</creator><creator>Noda, Setsuko</creator><creator>Sasaoka, Masaki</creator><creator>Shimazaki, Atsushi</creator><creator>Takada, Yuichiro</creator><creator>Iwata, Takeshi</creator><general>Oxford University Press</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20100701</creationdate><title>Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c543t-93519c91e1b6071e1704c186f82e166869ed39653073c0d884b2ff0fe71686823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Eye Proteins - genetics</topic><topic>Eye Proteins - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>Glaucoma - genetics</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred Strains</topic><topic>Mice, Transgenic</topic><topic>Molecular and cellular biology</topic><topic>Mutant Proteins - genetics</topic><topic>Mutant Proteins - metabolism</topic><topic>Ophthalmology</topic><topic>Optic Nerve - pathology</topic><topic>Protein Binding</topic><topic>rab GTP-Binding Proteins - metabolism</topic><topic>Retinal Degeneration - genetics</topic><topic>Retinal Ganglion Cells - pathology</topic><topic>Retinopathies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chi, Zai-Long</creatorcontrib><creatorcontrib>Akahori, Masakazu</creatorcontrib><creatorcontrib>Obazawa, Minoru</creatorcontrib><creatorcontrib>Minami, Masayoshi</creatorcontrib><creatorcontrib>Noda, Toru</creatorcontrib><creatorcontrib>Nakaya, Naoki</creatorcontrib><creatorcontrib>Tomarev, Stanislav</creatorcontrib><creatorcontrib>Kawase, Kazuhide</creatorcontrib><creatorcontrib>Yamamoto, Tetsuya</creatorcontrib><creatorcontrib>Noda, Setsuko</creatorcontrib><creatorcontrib>Sasaoka, Masaki</creatorcontrib><creatorcontrib>Shimazaki, Atsushi</creatorcontrib><creatorcontrib>Takada, Yuichiro</creatorcontrib><creatorcontrib>Iwata, Takeshi</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chi, Zai-Long</au><au>Akahori, Masakazu</au><au>Obazawa, Minoru</au><au>Minami, Masayoshi</au><au>Noda, Toru</au><au>Nakaya, Naoki</au><au>Tomarev, Stanislav</au><au>Kawase, Kazuhide</au><au>Yamamoto, Tetsuya</au><au>Noda, Setsuko</au><au>Sasaoka, Masaki</au><au>Shimazaki, Atsushi</au><au>Takada, Yuichiro</au><au>Iwata, Takeshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2010-07-01</date><risdate>2010</risdate><volume>19</volume><issue>13</issue><spage>2606</spage><epage>2615</epage><pages>2606-2615</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><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.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>20388642</pmid><doi>10.1093/hmg/ddq146</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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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 |
title | Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice |
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