Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria
Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, t...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2006-03, Vol.311 (5767), p.1621-1623 |
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| creator | Fong, Loren G Frost, David Meta, Margarita Qiao, Xin Yang, Shao H Coffinier, Catherine Young, Stephen G |
| description | Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria. |
| doi_str_mv | 10.1126/science.1124875 |
| format | Article |
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Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1124875</identifier><identifier>PMID: 16484451</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Aging ; Animals ; Biological and medical sciences ; Body weight ; Body Weight - drug effects ; Cell nucleus ; Dermatology ; Disease models ; Disease Models, Animal ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Farnesyltranstransferase - antagonists & inhibitors ; Female ; Female animals ; Genetic disorders ; Hand Strength ; Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue ; Imidazoles - pharmacology ; Imidazoles - therapeutic use ; Lamin Type A ; Male ; Male animals ; Medical sciences ; Membrane Proteins - deficiency ; Membrane Proteins - genetics ; Metalloendopeptidases - deficiency ; Metalloendopeptidases - genetics ; Mice ; Mutation ; Nuclear Proteins - metabolism ; Phenotypes ; Progeria ; Progeria - drug therapy ; Progeria - physiopathology ; Protein Precursors - metabolism ; Protein Prenylation - drug effects ; Proteins ; Rib fractures ; Rib Fractures - prevention & control ; Rodents ; Survival Rate ; Vehicles</subject><ispartof>Science (American Association for the Advancement of Science), 2006-03, Vol.311 (5767), p.1621-1623</ispartof><rights>Copyright 2006 American Association for the Advancement of Science</rights><rights>2007 INIST-CNRS</rights><rights>Copyright American Association for the Advancement of Science Mar 17, 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c582t-cc2108b09312c61257eaf4bd71cde63ae5736975fcbfc011268b3ee617f9deca3</citedby><cites>FETCH-LOGICAL-c582t-cc2108b09312c61257eaf4bd71cde63ae5736975fcbfc011268b3ee617f9deca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3845675$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3845675$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,780,784,803,2884,2885,27924,27925,58017,58250</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17702997$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16484451$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fong, Loren G</creatorcontrib><creatorcontrib>Frost, David</creatorcontrib><creatorcontrib>Meta, Margarita</creatorcontrib><creatorcontrib>Qiao, Xin</creatorcontrib><creatorcontrib>Yang, Shao H</creatorcontrib><creatorcontrib>Coffinier, Catherine</creatorcontrib><creatorcontrib>Young, Stephen G</creatorcontrib><title>Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.</description><subject>Aging</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Body weight</subject><subject>Body Weight - drug effects</subject><subject>Cell nucleus</subject><subject>Dermatology</subject><subject>Disease models</subject><subject>Disease Models, Animal</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Farnesyltranstransferase - antagonists & inhibitors</subject><subject>Female</subject><subject>Female animals</subject><subject>Genetic disorders</subject><subject>Hand Strength</subject><subject>Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue</subject><subject>Imidazoles - pharmacology</subject><subject>Imidazoles - therapeutic use</subject><subject>Lamin Type A</subject><subject>Male</subject><subject>Male animals</subject><subject>Medical sciences</subject><subject>Membrane Proteins - deficiency</subject><subject>Membrane Proteins - genetics</subject><subject>Metalloendopeptidases - deficiency</subject><subject>Metalloendopeptidases - genetics</subject><subject>Mice</subject><subject>Mutation</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phenotypes</subject><subject>Progeria</subject><subject>Progeria - drug therapy</subject><subject>Progeria - physiopathology</subject><subject>Protein Precursors - metabolism</subject><subject>Protein Prenylation - drug effects</subject><subject>Proteins</subject><subject>Rib fractures</subject><subject>Rib Fractures - prevention & control</subject><subject>Rodents</subject><subject>Survival Rate</subject><subject>Vehicles</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1rFTEUxYMo9llduxEdBN2NvUkmX8tSrRZaFLRuQyZzU_OYN2mTeYv-92Z4gwU3XSXh_HJuTg4hryl8opTJk-IjTh6XQ6eVeEI2FIxoDQP-lGwAuGw1KHFEXpSyBaia4c_JEZWd7jpBN-T3j5xmjFNz7vKE5X6cs5tKwOwKNhfTn9jHOeXmdIdjTNnNWJrPseCi1kuuuUr7ur1KA45NCk11u8Ec3UvyLLix4Kt1PSbX519-nX1rL79_vTg7vWy90GxuvWcUdA-GU-YlZUKhC10_KOoHlNyhUFwaJYLvg4clse45oqQqmAG948fk48H3Nqe7PZbZ7mLxOI5uwvoyK5WqFiAfBZkGIZVWj4JUUSqMNBV8_x-4Tfs81bSWUS60krC4nRwgn1MpGYO9zXHn8r2lYJc8dm3Qrg3WG29X232_w-GBXyurwIcVcMW7MdS-fCwPnFLAjFlGvzlw21Ib_Kdz3dWgy5x3Bzm4ZN1NrhbXPxlQDhRk_WfN_wLi1Lcw</recordid><startdate>20060317</startdate><enddate>20060317</enddate><creator>Fong, Loren G</creator><creator>Frost, David</creator><creator>Meta, Margarita</creator><creator>Qiao, Xin</creator><creator>Yang, Shao H</creator><creator>Coffinier, Catherine</creator><creator>Young, Stephen G</creator><general>American Association for the Advancement of Science</general><general>The American Association for the Advancement of Science</general><scope>FBQ</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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20060317</creationdate><title>Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria</title><author>Fong, Loren G ; Frost, David ; Meta, Margarita ; Qiao, Xin ; Yang, Shao H ; Coffinier, Catherine ; Young, Stephen G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c582t-cc2108b09312c61257eaf4bd71cde63ae5736975fcbfc011268b3ee617f9deca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Aging</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Body weight</topic><topic>Body Weight - drug effects</topic><topic>Cell nucleus</topic><topic>Dermatology</topic><topic>Disease models</topic><topic>Disease Models, Animal</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Farnesyltranstransferase - antagonists & inhibitors</topic><topic>Female</topic><topic>Female animals</topic><topic>Genetic disorders</topic><topic>Hand Strength</topic><topic>Hereditary diseases of the skin. 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Haemangioma of the skin, of mucosae and of soft tissue</topic><topic>Imidazoles - pharmacology</topic><topic>Imidazoles - therapeutic use</topic><topic>Lamin Type A</topic><topic>Male</topic><topic>Male animals</topic><topic>Medical sciences</topic><topic>Membrane Proteins - deficiency</topic><topic>Membrane Proteins - genetics</topic><topic>Metalloendopeptidases - deficiency</topic><topic>Metalloendopeptidases - genetics</topic><topic>Mice</topic><topic>Mutation</topic><topic>Nuclear Proteins - metabolism</topic><topic>Phenotypes</topic><topic>Progeria</topic><topic>Progeria - drug therapy</topic><topic>Progeria - physiopathology</topic><topic>Protein Precursors - metabolism</topic><topic>Protein Prenylation - drug effects</topic><topic>Proteins</topic><topic>Rib fractures</topic><topic>Rib Fractures - prevention & control</topic><topic>Rodents</topic><topic>Survival Rate</topic><topic>Vehicles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fong, Loren G</creatorcontrib><creatorcontrib>Frost, David</creatorcontrib><creatorcontrib>Meta, Margarita</creatorcontrib><creatorcontrib>Qiao, Xin</creatorcontrib><creatorcontrib>Yang, Shao H</creatorcontrib><creatorcontrib>Coffinier, Catherine</creatorcontrib><creatorcontrib>Young, Stephen G</creatorcontrib><collection>AGRIS</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>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fong, Loren G</au><au>Frost, David</au><au>Meta, Margarita</au><au>Qiao, Xin</au><au>Yang, Shao H</au><au>Coffinier, Catherine</au><au>Young, Stephen G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2006-03-17</date><risdate>2006</risdate><volume>311</volume><issue>5767</issue><spage>1621</spage><epage>1623</epage><pages>1621-1623</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.</abstract><cop>Washington, DC</cop><pub>American Association for the Advancement of Science</pub><pmid>16484451</pmid><doi>10.1126/science.1124875</doi><tpages>3</tpages></addata></record> |
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| ispartof | Science (American Association for the Advancement of Science), 2006-03, Vol.311 (5767), p.1621-1623 |
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| subjects | Aging Animals Biological and medical sciences Body weight Body Weight - drug effects Cell nucleus Dermatology Disease models Disease Models, Animal Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Farnesyltranstransferase - antagonists & inhibitors Female Female animals Genetic disorders Hand Strength Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue Imidazoles - pharmacology Imidazoles - therapeutic use Lamin Type A Male Male animals Medical sciences Membrane Proteins - deficiency Membrane Proteins - genetics Metalloendopeptidases - deficiency Metalloendopeptidases - genetics Mice Mutation Nuclear Proteins - metabolism Phenotypes Progeria Progeria - drug therapy Progeria - physiopathology Protein Precursors - metabolism Protein Prenylation - drug effects Proteins Rib fractures Rib Fractures - prevention & control Rodents Survival Rate Vehicles |
| title | Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria |
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