Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes
UBQLN1 variants have been associated with increased risk for late-onset Alzheimer’s disease (AD). We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1, dUbqln. Silencing of dUbqln in the central nervous system led to age-depend...
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| Veröffentlicht in: | Human molecular genetics 2007-11, Vol.16 (21), p.2626-2639 |
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| creator | Li, Airong Xie, Zhongcong Dong, Yuanlin McKay, Kenneth M. McKee, Mary L. Tanzi, Rudolph E. |
| description | UBQLN1 variants have been associated with increased risk for late-onset Alzheimer’s disease (AD). We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1, dUbqln. Silencing of dUbqln in the central nervous system led to age-dependent neurodegeneration and shortened lifespan. Silencing of dUbqln in the wing led to wing vein loss that could be partially rescued by mutant rhomboid (rho), a known component of epidermal growth factor receptor signaling pathway. Conversely, overexpression of dUbqln promoted ecotopic wing veins. Overexpression of dUbqln in the eye rescued a small, rough eye phenotype induced by overexpression of Drosophila presenilin (dPsn), and also rescuing dPsn-induced malformations in bristles. In contrast, RNAi silencing of dUbqln enhanced the retinal degenerative defect induced by overexpression of dPsn. Finally, co-overexpression of dUbqln and the human amyloid precursor protein (APP) in the eye significantly reduced the levels of full-length APP and its C-terminal fragment. Collectively, these data support in vivo functional interaction between UBQLN1 and the AD-associated genes, presenilin and APP, and provide further clues regarding the potential role of UBQLN1 in AD pathogenesis. |
| doi_str_mv | 10.1093/hmg/ddm219 |
| format | Article |
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We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1, dUbqln. Silencing of dUbqln in the central nervous system led to age-dependent neurodegeneration and shortened lifespan. Silencing of dUbqln in the wing led to wing vein loss that could be partially rescued by mutant rhomboid (rho), a known component of epidermal growth factor receptor signaling pathway. Conversely, overexpression of dUbqln promoted ecotopic wing veins. Overexpression of dUbqln in the eye rescued a small, rough eye phenotype induced by overexpression of Drosophila presenilin (dPsn), and also rescuing dPsn-induced malformations in bristles. In contrast, RNAi silencing of dUbqln enhanced the retinal degenerative defect induced by overexpression of dPsn. Finally, co-overexpression of dUbqln and the human amyloid precursor protein (APP) in the eye significantly reduced the levels of full-length APP and its C-terminal fragment. Collectively, these data support in vivo functional interaction between UBQLN1 and the AD-associated genes, presenilin and APP, and provide further clues regarding the potential role of UBQLN1 in AD pathogenesis.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddm219</identifier><identifier>PMID: 17704509</identifier><identifier>CODEN: HNGEE5</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Alzheimer Disease - genetics ; Alzheimer Disease - metabolism ; Amyloid beta-Protein Precursor - genetics ; Amyloid beta-Protein Precursor - metabolism ; Animals ; Animals, Genetically Modified ; Body Patterning - genetics ; Carrier Proteins - antagonists & inhibitors ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Cycle Proteins - antagonists & inhibitors ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Disease Models, Animal ; Drosophila ; Drosophila - genetics ; Drosophila - growth & development ; Drosophila - metabolism ; Drosophila Proteins - analysis ; Drosophila Proteins - genetics ; Drosophila Proteins - metabolism ; Humans ; Molecular Sequence Data ; Presenilins - analysis ; Presenilins - genetics ; Presenilins - metabolism ; Retina - chemistry ; Retina - metabolism ; Wings, Animal - embryology</subject><ispartof>Human molecular genetics, 2007-11, Vol.16 (21), p.2626-2639</ispartof><rights>The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2007</rights><rights>The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-2dc88666b769809b01071863581056ced083b5bd618da6fc8386217806fae16f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17704509$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Airong</creatorcontrib><creatorcontrib>Xie, Zhongcong</creatorcontrib><creatorcontrib>Dong, Yuanlin</creatorcontrib><creatorcontrib>McKay, Kenneth M.</creatorcontrib><creatorcontrib>McKee, Mary L.</creatorcontrib><creatorcontrib>Tanzi, Rudolph E.</creatorcontrib><title>Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>UBQLN1 variants have been associated with increased risk for late-onset Alzheimer’s disease (AD). We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1, dUbqln. Silencing of dUbqln in the central nervous system led to age-dependent neurodegeneration and shortened lifespan. Silencing of dUbqln in the wing led to wing vein loss that could be partially rescued by mutant rhomboid (rho), a known component of epidermal growth factor receptor signaling pathway. Conversely, overexpression of dUbqln promoted ecotopic wing veins. Overexpression of dUbqln in the eye rescued a small, rough eye phenotype induced by overexpression of Drosophila presenilin (dPsn), and also rescuing dPsn-induced malformations in bristles. In contrast, RNAi silencing of dUbqln enhanced the retinal degenerative defect induced by overexpression of dPsn. Finally, co-overexpression of dUbqln and the human amyloid precursor protein (APP) in the eye significantly reduced the levels of full-length APP and its C-terminal fragment. Collectively, these data support in vivo functional interaction between UBQLN1 and the AD-associated genes, presenilin and APP, and provide further clues regarding the potential role of UBQLN1 in AD pathogenesis.</description><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - metabolism</subject><subject>Amyloid beta-Protein Precursor - genetics</subject><subject>Amyloid beta-Protein Precursor - metabolism</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Body Patterning - genetics</subject><subject>Carrier Proteins - antagonists & inhibitors</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Cycle Proteins - antagonists & inhibitors</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Disease Models, Animal</subject><subject>Drosophila</subject><subject>Drosophila - genetics</subject><subject>Drosophila - growth & development</subject><subject>Drosophila - metabolism</subject><subject>Drosophila Proteins - analysis</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - metabolism</subject><subject>Humans</subject><subject>Molecular Sequence Data</subject><subject>Presenilins - analysis</subject><subject>Presenilins - genetics</subject><subject>Presenilins - metabolism</subject><subject>Retina - chemistry</subject><subject>Retina - metabolism</subject><subject>Wings, Animal - embryology</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQhy0EoqVw4QGQhQQHpNBxnEyc3qryZyst4gCVEBfLiZ2NixPv2kmhfQIeG6-yAokDnEaa-fRpZn6EPGXwmkHNT_thc6r1kLP6HjlmBUKWg-D3yTHUWGRYAx6RRzFeAzAsePWQHLGqgqKE-pj8vIzeqcn6kapR07ZXQbWTCfZuafqOTr2hb4KPfttbp-jc2N1snU2zMPXe-Q3VV83OjWc09W7sjU81GZJmL_hup54aFdxt5sdoJnru7npjBxOottGoaOjGjCY-Jg865aJ5cqgn5Ord288Xq2z98f3lxfk6a4uimrJct0IgYlNhLaBugEHFBPJSMCixNTpd3pSNRia0wq4VXGDOKgHYKcOw4yfk5eLdBr-bTZzkYGNrnFOj8XOUKAqAsuT_BXMo9ivkCXz-F3jt5zCmI2TOGOdFnmOCXi1Qmz4Zg-nkNthBhVvJQO5TlClFuaSY4GcH49wMRv9BD7El4MUC-Hn7b1G2cDZO5sdvUoVvEitelXL15atkuOZQf1jJT_wXrQ61gQ</recordid><startdate>20071101</startdate><enddate>20071101</enddate><creator>Li, Airong</creator><creator>Xie, Zhongcong</creator><creator>Dong, Yuanlin</creator><creator>McKay, Kenneth M.</creator><creator>McKee, Mary L.</creator><creator>Tanzi, Rudolph E.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</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>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7SS</scope><scope>7X8</scope></search><sort><creationdate>20071101</creationdate><title>Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes</title><author>Li, Airong ; Xie, Zhongcong ; Dong, Yuanlin ; McKay, Kenneth M. ; McKee, Mary L. ; Tanzi, Rudolph E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-2dc88666b769809b01071863581056ced083b5bd618da6fc8386217806fae16f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - metabolism</topic><topic>Amyloid beta-Protein Precursor - genetics</topic><topic>Amyloid beta-Protein Precursor - metabolism</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Body Patterning - genetics</topic><topic>Carrier Proteins - antagonists & inhibitors</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Cycle Proteins - antagonists & inhibitors</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Disease Models, Animal</topic><topic>Drosophila</topic><topic>Drosophila - genetics</topic><topic>Drosophila - growth & development</topic><topic>Drosophila - metabolism</topic><topic>Drosophila Proteins - analysis</topic><topic>Drosophila Proteins - genetics</topic><topic>Drosophila Proteins - metabolism</topic><topic>Humans</topic><topic>Molecular Sequence Data</topic><topic>Presenilins - analysis</topic><topic>Presenilins - genetics</topic><topic>Presenilins - metabolism</topic><topic>Retina - chemistry</topic><topic>Retina - metabolism</topic><topic>Wings, Animal - embryology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Airong</creatorcontrib><creatorcontrib>Xie, Zhongcong</creatorcontrib><creatorcontrib>Dong, Yuanlin</creatorcontrib><creatorcontrib>McKay, Kenneth M.</creatorcontrib><creatorcontrib>McKee, Mary L.</creatorcontrib><creatorcontrib>Tanzi, Rudolph E.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>MEDLINE - Academic</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Airong</au><au>Xie, Zhongcong</au><au>Dong, Yuanlin</au><au>McKay, Kenneth M.</au><au>McKee, Mary L.</au><au>Tanzi, Rudolph E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2007-11-01</date><risdate>2007</risdate><volume>16</volume><issue>21</issue><spage>2626</spage><epage>2639</epage><pages>2626-2639</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><coden>HNGEE5</coden><abstract>UBQLN1 variants have been associated with increased risk for late-onset Alzheimer’s disease (AD). We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1, dUbqln. Silencing of dUbqln in the central nervous system led to age-dependent neurodegeneration and shortened lifespan. Silencing of dUbqln in the wing led to wing vein loss that could be partially rescued by mutant rhomboid (rho), a known component of epidermal growth factor receptor signaling pathway. Conversely, overexpression of dUbqln promoted ecotopic wing veins. Overexpression of dUbqln in the eye rescued a small, rough eye phenotype induced by overexpression of Drosophila presenilin (dPsn), and also rescuing dPsn-induced malformations in bristles. In contrast, RNAi silencing of dUbqln enhanced the retinal degenerative defect induced by overexpression of dPsn. Finally, co-overexpression of dUbqln and the human amyloid precursor protein (APP) in the eye significantly reduced the levels of full-length APP and its C-terminal fragment. Collectively, these data support in vivo functional interaction between UBQLN1 and the AD-associated genes, presenilin and APP, and provide further clues regarding the potential role of UBQLN1 in AD pathogenesis.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>17704509</pmid><doi>10.1093/hmg/ddm219</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals |
| subjects | Alzheimer Disease - genetics Alzheimer Disease - metabolism Amyloid beta-Protein Precursor - genetics Amyloid beta-Protein Precursor - metabolism Animals Animals, Genetically Modified Body Patterning - genetics Carrier Proteins - antagonists & inhibitors Carrier Proteins - genetics Carrier Proteins - metabolism Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Disease Models, Animal Drosophila Drosophila - genetics Drosophila - growth & development Drosophila - metabolism Drosophila Proteins - analysis Drosophila Proteins - genetics Drosophila Proteins - metabolism Humans Molecular Sequence Data Presenilins - analysis Presenilins - genetics Presenilins - metabolism Retina - chemistry Retina - metabolism Wings, Animal - embryology |
| title | Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes |
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