Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
Identifieur interne : 000E20 ( Main/Exploration ); précédent : 000E19; suivant : 000E21Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
Auteurs : Hazel Urwin ; Astrid Authier ; Jorgen E. Nielsen ; Daniel Metcalf ; Caroline Powell ; Kristina Froud ; Denise S. Malcolm ; Ida Holm ; Peter Johannsen ; Jeremy Brown ; Elizabeth M. C. Fisher ; Julie Van Der Zee ; Marc Bruyland ; Christine Van Broeckhoven ; John Collinge ; Sebastian Brandner ; Clare Futter [Royaume-Uni] ; Adrian M. Isaacs [Royaume-Uni]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-06-01.
Abstract
Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. We report a novel endosomal pathology in CHMP2B mutation-positive patient brains and also identify and characterize abnormal endosomes in patient fibroblasts. Functional studies demonstrate a specific disruption of endosomelysosome fusion but not protein sorting by the MVB. We provide evidence for a mechanism for impaired endosomelysosome fusion whereby mutant CHMP2B constitutively binds to MVBs and prevents recruitment of proteins necessary for fusion to occur, such as Rab7. The fusion of endosomes with lysosomes is required for neuronal function and the data presented therefore suggest a pathogenic mechanism for FTD caused by CHMP2B mutations.
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DOI: 10.1093/hmg/ddq100
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Isaacs</name><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-06-01">2010-06-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2228">2228</biblScope><biblScope unit="page" to="2238">2238</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">2CFEEE5802A5E735587CDF97177100EEABE0181E</idno><idno type="DOI">10.1093/hmg/ddq100</idno><idno type="ArticleID">ddq100</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. We report a novel endosomal pathology in CHMP2B mutation-positive patient brains and also identify and characterize abnormal endosomes in patient fibroblasts. Functional studies demonstrate a specific disruption of endosomelysosome fusion but not protein sorting by the MVB. We provide evidence for a mechanism for impaired endosomelysosome fusion whereby mutant CHMP2B constitutively binds to MVBs and prevents recruitment of proteins necessary for fusion to occur, such as Rab7. The fusion of endosomes with lysosomes is required for neuronal function and the data presented therefore suggest a pathogenic mechanism for FTD caused by CHMP2B mutations.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement></list><tree><noCountry><name sortKey="Authier, Astrid" sort="Authier, Astrid" uniqKey="Authier A" first="Astrid" last="Authier">Astrid Authier</name><name sortKey="Brandner, Sebastian" sort="Brandner, Sebastian" uniqKey="Brandner S" first="Sebastian" last="Brandner">Sebastian Brandner</name><name sortKey="Brown, Jeremy" sort="Brown, Jeremy" uniqKey="Brown J" first="Jeremy" last="Brown">Jeremy Brown</name><name sortKey="Bruyland, Marc" sort="Bruyland, Marc" uniqKey="Bruyland M" first="Marc" last="Bruyland">Marc Bruyland</name><name sortKey="Collinge, John" sort="Collinge, John" uniqKey="Collinge J" first="John" last="Collinge">John Collinge</name><name sortKey="Fisher, Elizabeth M C" sort="Fisher, Elizabeth M C" uniqKey="Fisher E" first="Elizabeth M. C." last="Fisher">Elizabeth M. C. Fisher</name><name sortKey="Froud, Kristina" sort="Froud, Kristina" uniqKey="Froud K" first="Kristina" last="Froud">Kristina Froud</name><name sortKey="Holm, Ida" sort="Holm, Ida" uniqKey="Holm I" first="Ida" last="Holm">Ida Holm</name><name sortKey="Johannsen, Peter" sort="Johannsen, Peter" uniqKey="Johannsen P" first="Peter" last="Johannsen">Peter Johannsen</name><name sortKey="Malcolm, Denise S" sort="Malcolm, Denise S" uniqKey="Malcolm D" first="Denise S." last="Malcolm">Denise S. Malcolm</name><name sortKey="Metcalf, Daniel" sort="Metcalf, Daniel" uniqKey="Metcalf D" first="Daniel" last="Metcalf">Daniel Metcalf</name><name sortKey="Nielsen, Jorgen E" sort="Nielsen, Jorgen E" uniqKey="Nielsen J" first="Jorgen E." last="Nielsen">Jorgen E. Nielsen</name><name sortKey="Powell, Caroline" sort="Powell, Caroline" uniqKey="Powell C" first="Caroline" last="Powell">Caroline Powell</name><name sortKey="Urwin, Hazel" sort="Urwin, Hazel" uniqKey="Urwin H" first="Hazel" last="Urwin">Hazel Urwin</name><name sortKey="Van Broeckhoven, Christine" sort="Van Broeckhoven, Christine" uniqKey="Van Broeckhoven C" first="Christine" last="Van Broeckhoven">Christine Van Broeckhoven</name><name sortKey="Van Der Zee, Julie" sort="Van Der Zee, Julie" uniqKey="Van Der Zee J" first="Julie" last="Van Der Zee">Julie Van Der Zee</name></noCountry><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Futter, Clare" sort="Futter, Clare" uniqKey="Futter C" first="Clare" last="Futter">Clare Futter</name></region><name sortKey="Isaacs, Adrian M" sort="Isaacs, Adrian M" uniqKey="Isaacs A" first="Adrian M." last="Isaacs">Adrian M. Isaacs</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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