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Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations.

Urwin H, Authier A, Nielsen JE, Metcalf D, Powell C, Froud K, Malcolm DS, Holm I, Johannsen P, Brown J, Fisher EM, van der Zee J, Bruyland M, FReJA ConsortiumVan Broeckhoven C, Collinge J, Brandner S, Futter C, Isaacs AM - Hum. Mol. Genet. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.

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.

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Mutant CHMP2B transcripts are expressed in patient brain. (A) Schematic diagram showing CHMP2BWildtype and the C-terminal truncations predicted by expression of the mutant transcripts. Grey indicates conservation of the wild-type protein, black indicates novel amino acids. Notably CHMP2BΔ10 includes a 29 amino acid C-terminal nonsense sequence. (B) Quantitative real-time PCR analysis of CHMP2B transcripts in three FTD-3 patient brains. CHMP2BIntron5 is expressed at ∼36% and CHMP2BΔ10 at ∼10% of CHMP2BWildtype levels.
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DDQ100F1: Mutant CHMP2B transcripts are expressed in patient brain. (A) Schematic diagram showing CHMP2BWildtype and the C-terminal truncations predicted by expression of the mutant transcripts. Grey indicates conservation of the wild-type protein, black indicates novel amino acids. Notably CHMP2BΔ10 includes a 29 amino acid C-terminal nonsense sequence. (B) Quantitative real-time PCR analysis of CHMP2B transcripts in three FTD-3 patient brains. CHMP2BIntron5 is expressed at ∼36% and CHMP2BΔ10 at ∼10% of CHMP2BWildtype levels.

Mentions: Analysis of the Jutland pedigree identified a disease segregating mutation in CHMP2B (4,5). This G>C transition in the 5′ acceptor splice site of exon 6 produces two aberrant transcripts: CHMP2BIntron5 and CHMP2BΔ10 (Fig. 1A). The proteins predicted from these splice variants are both C-terminal truncations of 36 amino acids (4). A CHMP2B nonsense mutation has been found in an unrelated familial FTD patient (6). This mutation (C493T) predicts replacement of a glutamine residue with a stop codon (CHMP2BQ165X) causing a C-terminal truncation of 49 amino acids (Fig. 1A).


Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations.

Urwin H, Authier A, Nielsen JE, Metcalf D, Powell C, Froud K, Malcolm DS, Holm I, Johannsen P, Brown J, Fisher EM, van der Zee J, Bruyland M, FReJA ConsortiumVan Broeckhoven C, Collinge J, Brandner S, Futter C, Isaacs AM - Hum. Mol. Genet. (2010)

Mutant CHMP2B transcripts are expressed in patient brain. (A) Schematic diagram showing CHMP2BWildtype and the C-terminal truncations predicted by expression of the mutant transcripts. Grey indicates conservation of the wild-type protein, black indicates novel amino acids. Notably CHMP2BΔ10 includes a 29 amino acid C-terminal nonsense sequence. (B) Quantitative real-time PCR analysis of CHMP2B transcripts in three FTD-3 patient brains. CHMP2BIntron5 is expressed at ∼36% and CHMP2BΔ10 at ∼10% of CHMP2BWildtype levels.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2865375&req=5

DDQ100F1: Mutant CHMP2B transcripts are expressed in patient brain. (A) Schematic diagram showing CHMP2BWildtype and the C-terminal truncations predicted by expression of the mutant transcripts. Grey indicates conservation of the wild-type protein, black indicates novel amino acids. Notably CHMP2BΔ10 includes a 29 amino acid C-terminal nonsense sequence. (B) Quantitative real-time PCR analysis of CHMP2B transcripts in three FTD-3 patient brains. CHMP2BIntron5 is expressed at ∼36% and CHMP2BΔ10 at ∼10% of CHMP2BWildtype levels.
Mentions: Analysis of the Jutland pedigree identified a disease segregating mutation in CHMP2B (4,5). This G>C transition in the 5′ acceptor splice site of exon 6 produces two aberrant transcripts: CHMP2BIntron5 and CHMP2BΔ10 (Fig. 1A). The proteins predicted from these splice variants are both C-terminal truncations of 36 amino acids (4). A CHMP2B nonsense mutation has been found in an unrelated familial FTD patient (6). This mutation (C493T) predicts replacement of a glutamine residue with a stop codon (CHMP2BQ165X) causing a C-terminal truncation of 49 amino acids (Fig. 1A).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.

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.

Show MeSH
Related in: MedlinePlus