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Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

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 e...

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Autores principales: Urwin, Hazel, Authier, Astrid, Nielsen, Jorgen E., Metcalf, Daniel, Powell, Caroline, Froud, Kristina, Malcolm, Denise S., Holm, Ida, Johannsen, Peter, Brown, Jeremy, Fisher, Elizabeth M.C., van der Zee, Julie, Bruyland, Marc, Van Broeckhoven, Christine, Collinge, John, Brandner, Sebastian, Futter, Clare, Isaacs, Adrian M.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865375/
https://www.ncbi.nlm.nih.gov/pubmed/20223751
http://dx.doi.org/10.1093/hmg/ddq100
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author Urwin, Hazel
Authier, Astrid
Nielsen, Jorgen E.
Metcalf, Daniel
Powell, Caroline
Froud, Kristina
Malcolm, Denise S.
Holm, Ida
Johannsen, Peter
Brown, Jeremy
Fisher, Elizabeth M.C.
van der Zee, Julie
Bruyland, Marc
Van Broeckhoven, Christine
Collinge, John
Brandner, Sebastian
Futter, Clare
Isaacs, Adrian M.
author_facet Urwin, Hazel
Authier, Astrid
Nielsen, Jorgen E.
Metcalf, Daniel
Powell, Caroline
Froud, Kristina
Malcolm, Denise S.
Holm, Ida
Johannsen, Peter
Brown, Jeremy
Fisher, Elizabeth M.C.
van der Zee, Julie
Bruyland, Marc
Van Broeckhoven, Christine
Collinge, John
Brandner, Sebastian
Futter, Clare
Isaacs, Adrian M.
author_sort Urwin, Hazel
collection PubMed
description 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 endosome–lysosome fusion but not protein sorting by the MVB. We provide evidence for a mechanism for impaired endosome–lysosome 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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spelling pubmed-28653752010-05-07 Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations Urwin, Hazel Authier, Astrid Nielsen, Jorgen E. Metcalf, Daniel Powell, Caroline Froud, Kristina Malcolm, Denise S. Holm, Ida Johannsen, Peter Brown, Jeremy Fisher, Elizabeth M.C. van der Zee, Julie Bruyland, Marc Van Broeckhoven, Christine Collinge, John Brandner, Sebastian Futter, Clare Isaacs, Adrian M. Hum Mol Genet Articles 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 endosome–lysosome fusion but not protein sorting by the MVB. We provide evidence for a mechanism for impaired endosome–lysosome 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. Oxford University Press 2010-06-01 2010-03-10 /pmc/articles/PMC2865375/ /pubmed/20223751 http://dx.doi.org/10.1093/hmg/ddq100 Text en © The Author 2010. Published by Oxford University Press http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Urwin, Hazel
Authier, Astrid
Nielsen, Jorgen E.
Metcalf, Daniel
Powell, Caroline
Froud, Kristina
Malcolm, Denise S.
Holm, Ida
Johannsen, Peter
Brown, Jeremy
Fisher, Elizabeth M.C.
van der Zee, Julie
Bruyland, Marc
Van Broeckhoven, Christine
Collinge, John
Brandner, Sebastian
Futter, Clare
Isaacs, Adrian M.
Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
title Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
title_full Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
title_fullStr Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
title_full_unstemmed Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
title_short Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
title_sort disruption of endocytic trafficking in frontotemporal dementia with chmp2b mutations
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865375/
https://www.ncbi.nlm.nih.gov/pubmed/20223751
http://dx.doi.org/10.1093/hmg/ddq100
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