A toxic monomeric conformer of the polyglutamine protein
Identifieur interne : 001131 ( Main/Exploration ); précédent : 001130; suivant : 001132A toxic monomeric conformer of the polyglutamine protein
Auteurs : Yoshitaka Nagai [Japon] ; Takashi Inui [Japon] ; H Akiko Popiel [Japon] ; Nobuhiro Fujikake [Japon] ; Kazuhiro Hasegawa [Japon] ; Yoshihiro Urade [Japon] ; Yuji Goto [Japon] ; Hironobu Naiki [Japon] ; Tatsushi Toda [Japon]Source :
- 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
Affiliations:
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565-0871</wicri:noRegion></affiliation></author><author><name sortKey="Fujikake, Nobuhiro" sort="Fujikake, Nobuhiro" uniqKey="Fujikake N" first="Nobuhiro" last="Fujikake">Nobuhiro Fujikake</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871</wicri:regionArea><wicri:noRegion>Osaka 565-0871</wicri:noRegion></affiliation></author><author><name sortKey="Hasegawa, Kazuhiro" sort="Hasegawa, Kazuhiro" uniqKey="Hasegawa K" first="Kazuhiro" last="Hasegawa">Kazuhiro Hasegawa</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Yoshida, Fukui 910-1193</wicri:regionArea><wicri:noRegion>Fukui 910-1193</wicri:noRegion></affiliation></author><author><name sortKey="Urade, Yoshihiro" sort="Urade, Yoshihiro" uniqKey="Urade Y" first="Yoshihiro" last="Urade">Yoshihiro Urade</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874</wicri:regionArea><wicri:noRegion>Osaka 565-0874</wicri:noRegion></affiliation></author><author><name sortKey="Goto, Yuji" sort="Goto, Yuji" uniqKey="Goto Y" first="Yuji" last="Goto">Yuji Goto</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Folding, Division of Protein Structural Biology, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871</wicri:regionArea><wicri:noRegion>Osaka 565-0871</wicri:noRegion></affiliation></author><author><name sortKey="Naiki, Hironobu" sort="Naiki, Hironobu" uniqKey="Naiki H" first="Hironobu" last="Naiki">Hironobu Naiki</name><affiliation wicri:level="1"><country 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Group</publisher><date type="published" when="2007-04">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><idno type="ISSN">1545-9993</idno></series><idno type="istex">6D8A01DFDC052A0DEDA5F0E067F22281382334D8</idno><idno type="DOI">10.1038/nsmb1215</idno><idno type="ArticleID">nsmb1215</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1545-9993</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml: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.</div></front></TEI><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Nagai, Yoshitaka" sort="Nagai, Yoshitaka" uniqKey="Nagai Y" first="Yoshitaka" last="Nagai">Yoshitaka Nagai</name></noRegion><name sortKey="Fujikake, Nobuhiro" sort="Fujikake, Nobuhiro" uniqKey="Fujikake N" first="Nobuhiro" last="Fujikake">Nobuhiro Fujikake</name><name sortKey="Goto, Yuji" sort="Goto, Yuji" uniqKey="Goto Y" first="Yuji" last="Goto">Yuji Goto</name><name sortKey="Hasegawa, Kazuhiro" sort="Hasegawa, Kazuhiro" uniqKey="Hasegawa K" first="Kazuhiro" last="Hasegawa">Kazuhiro Hasegawa</name><name sortKey="Inui, Takashi" sort="Inui, Takashi" uniqKey="Inui T" first="Takashi" last="Inui">Takashi Inui</name><name sortKey="Inui, Takashi" sort="Inui, Takashi" uniqKey="Inui T" first="Takashi" last="Inui">Takashi Inui</name><name sortKey="Inui, Takashi" sort="Inui, Takashi" uniqKey="Inui T" first="Takashi" last="Inui">Takashi Inui</name><name sortKey="Nagai, Yoshitaka" sort="Nagai, Yoshitaka" uniqKey="Nagai Y" first="Yoshitaka" last="Nagai">Yoshitaka Nagai</name><name sortKey="Naiki, Hironobu" sort="Naiki, Hironobu" uniqKey="Naiki H" first="Hironobu" last="Naiki">Hironobu Naiki</name><name sortKey="Popiel, H Akiko" sort="Popiel, H Akiko" uniqKey="Popiel H" first="H Akiko" last="Popiel">H Akiko Popiel</name><name sortKey="Toda, Tatsushi" sort="Toda, Tatsushi" uniqKey="Toda T" first="Tatsushi" last="Toda">Tatsushi Toda</name><name sortKey="Toda, Tatsushi" sort="Toda, Tatsushi" uniqKey="Toda T" first="Tatsushi" last="Toda">Tatsushi Toda</name><name sortKey="Urade, Yoshihiro" sort="Urade, Yoshihiro" uniqKey="Urade Y" first="Yoshihiro" last="Urade">Yoshihiro Urade</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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