A toxic monomeric conformer of the polyglutamine protein
Identifieur interne : 001A06 ( Main/Corpus ); précédent : 001A05; suivant : 001A07A toxic monomeric conformer of the polyglutamine protein
Auteurs : Yoshitaka Nagai ; Takashi Inui ; H Akiko Popiel ; Nobuhiro Fujikake ; Kazuhiro Hasegawa ; Yoshihiro Urade ; Yuji Goto ; Hironobu Naiki ; Tatsushi TodaSource :
- Nature Structural & Molecular Biology [ 1545-9993 ] ; 2007-04.
Abstract
Polyglutamine (polyQ) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a -sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into -sheetrich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble -sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic -sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.
Url:
DOI: 10.1038/nsmb1215
Links to Exploration step
ISTEX:6D8A01DFDC052A0DEDA5F0E067F22281382334D8Le document en format XML
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Japan.</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Food and Nutrition, Tsu City College, Tsu, Mie 514-0112, Japan.</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</mods:affiliation></affiliation></author><author><name sortKey="Popiel, H Akiko" sort="Popiel, H Akiko" uniqKey="Popiel H" first="H Akiko" last="Popiel">H Akiko Popiel</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</mods:affiliation></affiliation></author><author><name sortKey="Fujikake, Nobuhiro" sort="Fujikake, Nobuhiro" uniqKey="Fujikake N" first="Nobuhiro" last="Fujikake">Nobuhiro Fujikake</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 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Nobuhiro" uniqKey="Fujikake N" first="Nobuhiro" last="Fujikake">Nobuhiro Fujikake</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</mods:affiliation></affiliation></author><author><name sortKey="Hasegawa, Kazuhiro" sort="Hasegawa, Kazuhiro" uniqKey="Hasegawa K" first="Kazuhiro" last="Hasegawa">Kazuhiro Hasegawa</name><affiliation><mods:affiliation>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</mods:affiliation></affiliation></author><author><name sortKey="Urade, Yoshihiro" sort="Urade, Yoshihiro" uniqKey="Urade Y" first="Yoshihiro" last="Urade">Yoshihiro Urade</name><affiliation><mods:affiliation>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</mods:affiliation></affiliation></author><author><name sortKey="Goto, Yuji" sort="Goto, Yuji" uniqKey="Goto Y" first="Yuji" last="Goto">Yuji Goto</name><affiliation><mods:affiliation>Laboratory of Protein Folding, Division of Protein Structural Biology, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.</mods:affiliation></affiliation></author><author><name sortKey="Naiki, Hironobu" sort="Naiki, Hironobu" uniqKey="Naiki H" first="Hironobu" last="Naiki">Hironobu Naiki</name><affiliation><mods:affiliation>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</mods:affiliation></affiliation></author><author><name sortKey="Toda, Tatsushi" sort="Toda, Tatsushi" uniqKey="Toda T" first="Tatsushi" last="Toda">Tatsushi Toda</name><affiliation><mods:affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, 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However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a -sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into -sheetrich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble -sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic -sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.</div></front></TEI><istex><corpusName>nature</corpusName><author><json:item><name>Yoshitaka Nagai</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</json:string><json:string>E-mail: nagai@clgene.med.osaka-u.ac.jp</json:string></affiliations></json:item><json:item><name>Takashi Inui</name><affiliations><json:string>Department of Molecular Biology and Cell Informatics, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.</json:string><json:string>Department of Food and Nutrition, Tsu City College, Tsu, Mie 514-0112, Japan.</json:string><json:string>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</json:string></affiliations></json:item><json:item><name>H Akiko Popiel</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</json:string></affiliations></json:item><json:item><name>Nobuhiro Fujikake</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</json:string></affiliations></json:item><json:item><name>Kazuhiro Hasegawa</name><affiliations><json:string>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</json:string></affiliations></json:item><json:item><name>Yoshihiro Urade</name><affiliations><json:string>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</json:string></affiliations></json:item><json:item><name>Yuji Goto</name><affiliations><json:string>Laboratory of Protein Folding, Division of Protein Structural Biology, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.</json:string></affiliations></json:item><json:item><name>Hironobu Naiki</name><affiliations><json:string>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</json:string></affiliations></json:item><json:item><name>Tatsushi Toda</name><affiliations><json:string>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</json:string><json:string>E-mail: toda@clgene.med.osaka-u.ac.jp</json:string></affiliations></json:item></author><language><json:string>eng</json:string></language><abstract>Polyglutamine (polyQ) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a -sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into -sheetrich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble -sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic -sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.</abstract><qualityIndicators><score>7.608</score><pdfVersion>1.5</pdfVersion><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1003</abstractCharCount><pdfWordCount>7712</pdfWordCount><pdfCharCount>51712</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>134</abstractWordCount></qualityIndicators><title>A toxic monomeric conformer of the polyglutamine protein</title><genre><json:string>research-article</json:string></genre><host><volume>14</volume><pages><total>9</total><last>340</last><first>332</first></pages><issn><json:string>1545-9993</json:string></issn><issue>4</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1545-9985</json:string></eissn><title>Nature 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toxic monomeric conformer of the polyglutamine protein</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Nature Publishing Group</publisher><availability><p>NATURE</p></availability><date>2007</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">A toxic monomeric conformer of the polyglutamine protein</title><author><persName><forename type="first">Yoshitaka</forename><surname>Nagai</surname></persName><email>nagai@clgene.med.osaka-u.ac.jp</email><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation></author><author><persName><forename type="first">Takashi</forename><surname>Inui</surname></persName><affiliation>Department of Molecular Biology and Cell Informatics, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.</affiliation><affiliation>Department of Food and Nutrition, Tsu City College, Tsu, Mie 514-0112, Japan.</affiliation><affiliation>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</affiliation></author><author><persName><forename type="first">H Akiko</forename><surname>Popiel</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation></author><author><persName><forename type="first">Nobuhiro</forename><surname>Fujikake</surname></persName><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation></author><author><persName><forename type="first">Kazuhiro</forename><surname>Hasegawa</surname></persName><affiliation>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</affiliation></author><author><persName><forename type="first">Yoshihiro</forename><surname>Urade</surname></persName><affiliation>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</affiliation></author><author><persName><forename type="first">Yuji</forename><surname>Goto</surname></persName><affiliation>Laboratory of Protein Folding, Division of Protein Structural Biology, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.</affiliation></author><author><persName><forename type="first">Hironobu</forename><surname>Naiki</surname></persName><affiliation>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</affiliation></author><author><persName><forename type="first">Tatsushi</forename><surname>Toda</surname></persName><email>toda@clgene.med.osaka-u.ac.jp</email><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation></author></analytic><monogr><title level="j">Nature Structural & Molecular Biology</title><idno type="pISSN">1545-9993</idno><idno type="eISSN">1545-9985</idno><imprint><publisher>Nature Publishing Group</publisher><date type="published" when="2007-04"></date><biblScope unit="volume">14</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="332">332</biblScope><biblScope unit="page" to="340">340</biblScope></imprint></monogr><idno type="istex">6D8A01DFDC052A0DEDA5F0E067F22281382334D8</idno><idno type="DOI">10.1038/nsmb1215</idno><idno type="ArticleID">nsmb1215</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2007</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Polyglutamine (polyQ) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a -sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into -sheetrich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble -sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic -sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.</p></abstract></profileDesc><revisionDesc><change when="2006-06-16">Received</change><change when="2007-02-14">Registration</change><change when="2007-04">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/6D8A01DFDC052A0DEDA5F0E067F22281382334D8/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus nature" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NPG//DTD XML Article//EN" URI="NPG_XML_Article.dtd" name="istex:docType"><istex:entity PUBLIC="-//NatureAmerica//FICI nsmb1215-F1//EN" URL="nsmb1215-F1" NDATA="ITEM" name="figf1"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nsmb1215-F2//EN" URL="nsmb1215-F2" NDATA="ITEM" name="figf2"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nsmb1215-F3//EN" URL="nsmb1215-F3" NDATA="ITEM" name="figf3"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nsmb1215-F4//EN" URL="nsmb1215-F4" NDATA="ITEM" name="figf4"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nsmb1215-F5//EN" URL="nsmb1215-F5" NDATA="ITEM" name="figf5"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nsmb1215-F6//EN" URL="nsmb1215-F6" NDATA="ITEM" name="figf6"></istex:entity><istex:entity SYSTEM="edsumm/nsmb1215-e1.xml" name="nsmb1215-e1"></istex:entity></istex:docType><istex:document><article id="nsmb1215" language="eng" relation="no"><pubfm><jtl>Nature Structural & Molecular Biology</jtl><vol>14</vol><iss>4</iss><idt>200704</idt><categ id="af"></categ><pp><spn>332</spn><epn>340</epn><cnt>9</cnt></pp><issn type="print">1545-9993</issn><issn type="electronic">1545-9985</issn><cpg><cpy>2007</cpy><cpn>Nature Publishing Group</cpn></cpg><doi>10.1038/nsmb1215</doi></pubfm><fm><atl>A toxic monomeric conformer of the polyglutamine protein</atl><aug><cau><fnm>Yoshitaka</fnm><snm>Nagai</snm><inits>Y</inits><orf rid="a1"></orf><corf rid="c1"></corf></cau><au><fnm>Takashi</fnm><snm>Inui</snm><inits>T</inits><orf rid="a2"></orf><orf rid="a3"></orf><orf rid="a4"></orf></au><au><fnm>H Akiko</fnm><snm>Popiel</snm><inits>H A</inits><orf rid="a1"></orf></au><au><fnm>Nobuhiro</fnm><snm>Fujikake</snm><inits>N</inits><orf rid="a1"></orf></au><au><fnm>Kazuhiro</fnm><snm>Hasegawa</snm><inits>K</inits><orf rid="a5"></orf></au><au><fnm>Yoshihiro</fnm><snm>Urade</snm><inits>Y</inits><orf rid="a4"></orf></au><au><fnm>Yuji</fnm><snm>Goto</snm><inits>Y</inits><orf rid="a6"></orf></au><au><fnm>Hironobu</fnm><snm>Naiki</snm><inits>H</inits><orf rid="a5"></orf></au><cau><fnm>Tatsushi</fnm><snm>Toda</snm><inits>T</inits><orf rid="a1"></orf><corf rid="c2"></corf></cau><aff><oid id="a1"></oid><org>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita</org>, <cty>Osaka</cty> <zip>565-0871</zip>, <cny>Japan</cny>.</aff><aff><oid id="a2"></oid><org>Department of Molecular Biology and Cell Informatics, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai</org>, <cty>Osaka</cty> <zip>599-8531</zip>, <cny>Japan</cny>.</aff><aff><oid id="a3"></oid><org>Department of Food and Nutrition, Tsu City College, Tsu</org>, <cty>Mie</cty> <zip>514-0112</zip>, <cny>Japan</cny>.</aff><aff><oid id="a4"></oid><org>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita</org>, <cty>Osaka</cty> <zip>565-0874</zip>, <cny>Japan</cny>.</aff><aff><oid id="a5"></oid><org>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida</org>, <cty>Fukui</cty> <zip>910-1193</zip>, <cny>Japan</cny>.</aff><aff><oid id="a6"></oid><org>Laboratory of Protein Folding, Division of Protein Structural Biology, Institute for Protein Research, Osaka University, Suita</org>, <cty>Osaka</cty> <zip>565-0871</zip>, <cny>Japan</cny>.</aff><caff><coid id="c1"></coid><email>nagai@clgene.med.osaka-u.ac.jp</email></caff><caff><coid id="c2"></coid><email>toda@clgene.med.osaka-u.ac.jp</email></caff></aug><hst><re year="2006" month="06" day="16"></re><acc year="2007" month="02" day="14"></acc><pubdate type="aop" year="2007" month="03" day="18"></pubdate></hst><abs><p>Polyglutamine (<scientific type="protein">polyQ</scientific>) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a β-sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into β-sheet–rich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble β-sheet monomer causes cytotoxicity. The polyQ-binding peptide <scientific type="protein">QBP1</scientific> prevents the toxic β-sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.</p></abs></fm></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="eng"><title>A toxic monomeric conformer of the polyglutamine protein</title></titleInfo><titleInfo type="alternative" lang="eng" contentType="CDATA"><title>A toxic monomeric conformer of the polyglutamine protein</title></titleInfo><name type="personal"><namePart type="given">Yoshitaka</namePart><namePart type="family">Nagai</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation><affiliation>E-mail: nagai@clgene.med.osaka-u.ac.jp</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Takashi</namePart><namePart type="family">Inui</namePart><affiliation>Department of Molecular Biology and Cell Informatics, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan.</affiliation><affiliation>Department of Food and Nutrition, Tsu City College, Tsu, Mie 514-0112, Japan.</affiliation><affiliation>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H Akiko</namePart><namePart type="family">Popiel</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nobuhiro</namePart><namePart type="family">Fujikake</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kazuhiro</namePart><namePart type="family">Hasegawa</namePart><affiliation>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yoshihiro</namePart><namePart type="family">Urade</namePart><affiliation>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yuji</namePart><namePart type="family">Goto</namePart><affiliation>Laboratory of Protein Folding, Division of Protein Structural Biology, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hironobu</namePart><namePart type="family">Naiki</namePart><affiliation>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193, Japan.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tatsushi</namePart><namePart type="family">Toda</namePart><affiliation>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.</affiliation><affiliation>E-mail: toda@clgene.med.osaka-u.ac.jp</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Article"></genre><originInfo><publisher>Nature Publishing Group</publisher><dateIssued encoding="w3cdtf">2007-04</dateIssued><dateCaptured encoding="w3cdtf">2006-06-16</dateCaptured><dateValid encoding="w3cdtf">2007-02-14</dateValid><copyrightDate encoding="w3cdtf">2007</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="eng">Polyglutamine (polyQ) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a -sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into -sheetrich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble -sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic -sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.</abstract><relatedItem type="host"><titleInfo><title>Nature Structural & Molecular Biology</title></titleInfo><identifier type="ISSN">1545-9993</identifier><identifier type="eISSN">1545-9985</identifier><part><date>2007</date><detail type="volume"><caption>vol.</caption><number>14</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>332</start><end>340</end><total>9</total></extent></part></relatedItem><identifier type="istex">6D8A01DFDC052A0DEDA5F0E067F22281382334D8</identifier><identifier type="DOI">10.1038/nsmb1215</identifier><identifier type="ArticleID">nsmb1215</identifier><accessCondition type="use and reproduction" contentType="copyright">©2007 Nature Publishing Group</accessCondition><recordInfo><recordContentSource>NATURE</recordContentSource></recordInfo></mods></metadata><covers><json:item><original>true</original><mimetype>image/gif</mimetype><extension>gif</extension><uri>https://api.istex.fr/document/6D8A01DFDC052A0DEDA5F0E067F22281382334D8/covers/gif</uri></json:item></covers><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/6D8A01DFDC052A0DEDA5F0E067F22281382334D8/annexes/jpeg</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/6D8A01DFDC052A0DEDA5F0E067F22281382334D8/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">BIOPHYSICS</classCode><classCode scheme="WOS">CELL BIOLOGY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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