Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
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Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. / Urwin, Hazel; Authier, Astrid; Nielsen, Jørgen Erik; 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; FReJA Consortium; Van Broeckhoven, Christine; Collinge, John; Brandner, Sebastian; Futter, Clare; Isaacs, Adrian M.
I: Human Molecular Genetics, Bind 19, Nr. 11, 2010, s. 2228-38.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations
AU - Urwin, Hazel
AU - Authier, Astrid
AU - Nielsen, Jørgen Erik
AU - Metcalf, Daniel
AU - Powell, Caroline
AU - Froud, Kristina
AU - Malcolm, Denise S
AU - Holm, Ida
AU - Johannsen, Peter
AU - Brown, Jeremy
AU - Fisher, Elizabeth M C
AU - van der Zee, Julie
AU - Bruyland, Marc
AU - FReJA Consortium
AU - Van Broeckhoven, Christine
AU - Collinge, John
AU - Brandner, Sebastian
AU - Futter, Clare
AU - Isaacs, Adrian M
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
U2 - 10.1093/hmg/ddq100
DO - 10.1093/hmg/ddq100
M3 - Journal article
C2 - 20223751
VL - 19
SP - 2228
EP - 2238
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 11
ER -
ID: 20970311