LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory
Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-07, Vol.115 (27), p.7111-7116 |
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creator | Seo, Bo Am Cho, Taesup Lee, Daniel Z. Lee, Joong-jae Lee, Boyoung Kim, Seong-Wook Shin, Hee-Sup Kang, Myoung-Goo |
description | Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability. |
doi_str_mv | 10.1073/pnas.1805060115 |
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How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1805060115</identifier><identifier>PMID: 29915039</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Brain ; Cognitive ability ; Dystrophy ; Genotype & phenotype ; Glutamic acid receptors ; Golgi apparatus ; Hippocampus - cytology ; Hippocampus - metabolism ; Humans ; Learning ; Long-term potentiation ; Long-Term Potentiation - physiology ; Memory ; Memory - physiology ; Mice ; Muscular dystrophy ; Mutation ; N-Acetylglucosaminyltransferases - genetics ; N-Acetylglucosaminyltransferases - metabolism ; Neurological disorders ; Overloading ; Protein transport ; Protein Transport - physiology ; Proteins ; Receptors, AMPA - genetics ; Receptors, AMPA - metabolism ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-07, Vol.115 (27), p.7111-7116</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Jul 3, 2018</rights><rights>2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-636be787398c6bf053e90be2fb0fb96d552853c7ce339d293580ed996eb4bf3c3</citedby><cites>FETCH-LOGICAL-c443t-636be787398c6bf053e90be2fb0fb96d552853c7ce339d293580ed996eb4bf3c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26511075$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26511075$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29915039$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seo, Bo Am</creatorcontrib><creatorcontrib>Cho, Taesup</creatorcontrib><creatorcontrib>Lee, Daniel Z.</creatorcontrib><creatorcontrib>Lee, Joong-jae</creatorcontrib><creatorcontrib>Lee, Boyoung</creatorcontrib><creatorcontrib>Kim, Seong-Wook</creatorcontrib><creatorcontrib>Shin, Hee-Sup</creatorcontrib><creatorcontrib>Kang, Myoung-Goo</creatorcontrib><title>LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Brain</subject><subject>Cognitive ability</subject><subject>Dystrophy</subject><subject>Genotype & phenotype</subject><subject>Glutamic acid receptors</subject><subject>Golgi apparatus</subject><subject>Hippocampus - cytology</subject><subject>Hippocampus - metabolism</subject><subject>Humans</subject><subject>Learning</subject><subject>Long-term potentiation</subject><subject>Long-Term Potentiation - physiology</subject><subject>Memory</subject><subject>Memory - physiology</subject><subject>Mice</subject><subject>Muscular dystrophy</subject><subject>Mutation</subject><subject>N-Acetylglucosaminyltransferases - genetics</subject><subject>N-Acetylglucosaminyltransferases - metabolism</subject><subject>Neurological disorders</subject><subject>Overloading</subject><subject>Protein transport</subject><subject>Protein Transport - physiology</subject><subject>Proteins</subject><subject>Receptors, AMPA - genetics</subject><subject>Receptors, AMPA - metabolism</subject><subject>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid</subject><subject>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUFv1DAQhS1ERZfCmRMoEhcOTTu2Yye-IK2qUpC2KkJwthxnsnhJ4tR2kPbf42pLCz1Zmvnmed48Qt5QOKNQ8_N5MvGMNiBAAqXiGVlRULSUlYLnZAXA6rKpWHVMXsa4AwAlGnhBjplSVABXKxI3629Xl6eFmQo3JRwGtGkxQ9G5aFo3uLQvTYzeOpOwK-bgE7rptAi4XYZcisX6-uu6TPsZi-2wJDPmYu5anJMPRQqm75395aZt_qErRhx92L8iR70ZIr6-f0_Ij0-X3y8-l5ubqy8X601pq4qnUnLZYt3UXDVWtj0IjgpaZH0LfatkJwRrBLe1Rc5VxxTP3rBTSmJbtT23_IR8POjOSztiZ3HK-wx6Dm40Ya-9cfr_zuR-6q3_rSWtGGtoFvhwLxD87YIx6dFFm49kJvRL1AxETamCRmX0_RN055cwZXuaUaCqhkqyTJ0fKBt8jAH7h2Uo6LtA9V2g-jHQPPHuXw8P_N8EM_D2AOxivvhjXwqaBQX_A2Sip-U</recordid><startdate>20180703</startdate><enddate>20180703</enddate><creator>Seo, Bo Am</creator><creator>Cho, Taesup</creator><creator>Lee, Daniel Z.</creator><creator>Lee, Joong-jae</creator><creator>Lee, Boyoung</creator><creator>Kim, Seong-Wook</creator><creator>Shin, Hee-Sup</creator><creator>Kang, Myoung-Goo</creator><general>National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180703</creationdate><title>LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory</title><author>Seo, Bo Am ; 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How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>29915039</pmid><doi>10.1073/pnas.1805060115</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biological Sciences Brain Cognitive ability Dystrophy Genotype & phenotype Glutamic acid receptors Golgi apparatus Hippocampus - cytology Hippocampus - metabolism Humans Learning Long-term potentiation Long-Term Potentiation - physiology Memory Memory - physiology Mice Muscular dystrophy Mutation N-Acetylglucosaminyltransferases - genetics N-Acetylglucosaminyltransferases - metabolism Neurological disorders Overloading Protein transport Protein Transport - physiology Proteins Receptors, AMPA - genetics Receptors, AMPA - metabolism α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors |
title | LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory |
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