Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

Hazel Urwin; Astrid Authier; Jørgen Erik 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; FReJA Consortium; Christine Van Broeckhoven; John Collinge; Sebastian Brandner; Clare Futter; Adrian M Isaacs

doi:10.1093/hmg/ddq100

Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

Hazel Urwin, Astrid Authier, Jørgen Erik 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, FReJA Consortium, Christine Van Broeckhoven, John Collinge, Sebastian Brandner, Clare Futter, Adrian M Isaacs

Medical Genetics Program

120 Citations (Scopus)

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 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.

Original language	English
Journal	Human Molecular Genetics
Volume	19
Issue number	11
Pages (from-to)	2228-38
Number of pages	10
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddq100
Publication status	Published - 10 Mar 2010

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Urwin, H., Authier, A., Nielsen, J. E., Metcalf, D., Powell, C., Froud, K., Malcolm, D. S., Holm, I., Johannsen, P., Brown, J., Fisher, E. M. C., van der Zee, J., Bruyland, M., FReJA Consortium, Van Broeckhoven, C., Collinge, J., Brandner, S., Futter, C., & Isaacs, A. M. (2010). Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Human Molecular Genetics, 19(11), 2228-38. https://doi.org/10.1093/hmg/ddq100

Urwin, H, Authier, A, Nielsen, JE, Metcalf, D, Powell, C, Froud, K, Malcolm, DS, Holm, I, Johannsen, P, Brown, J, Fisher, EMC, van der Zee, J, Bruyland, M, FReJA Consortium, Van Broeckhoven, C, Collinge, J, Brandner, S, Futter, C & Isaacs, AM 2010, 'Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations', Human Molecular Genetics, vol. 19, no. 11, pp. 2228-38. https://doi.org/10.1093/hmg/ddq100

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title = "Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations",

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 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.",

author = "Hazel Urwin and Astrid Authier and Nielsen, {J{\o}rgen Erik} and Daniel Metcalf and Caroline Powell and Kristina Froud and Malcolm, {Denise S} and Ida Holm and Peter Johannsen and Jeremy Brown and Fisher, {Elizabeth M C} and {van der Zee}, Julie and Marc Bruyland and {FReJA Consortium} and {Van Broeckhoven}, Christine and John Collinge and Sebastian Brandner and Clare Futter and Isaacs, {Adrian M}",

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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 - 2010/3/10

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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

SN - 0964-6906

VL - 19

SP - 2228

EP - 2238

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 11

ER -

Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations

Abstract

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