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Journal of neurology, neurosurgery, and psychiatry 12/2011; 82(12):1405-7. · 4.87 Impact Factor
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Hazel Urwin,
Keith A Josephs,
Jonathan D Rohrer,
Ian R Mackenzie,
Manuela Neumann,
Astrid Authier,
Harro Seelaar,
John C Van Swieten,
Jeremy M Brown,
Peter Johannsen, [......],
Valerie Doodeman,
Gary Adamson,
Shabnam Ghazi-Noori,
Elizabeth M C Fisher,
Janice L Holton,
Tamas Revesz,
Martin N Rossor,
John Collinge,
Simon Mead,
Adrian M Isaacs
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ABSTRACT: Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
Acta Neuropathologica 07/2010; 120(1):33-41. · 9.32 Impact Factor
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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,
Adrian M Isaacs
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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.
Human Molecular Genetics 03/2010; 19(11):2228-38. · 7.64 Impact Factor
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ABSTRACT: Mutations in the CHMP2B (charged multivesicular body protein 2B) gene that lead to C-terminal truncations of the protein can cause frontotemporal dementia. CHMP2B is a member of ESCRT-III (endosomal sorting complex required for transport III), which is required for formation of the multivesicular body, a late endosomal structure that fuses with the lysosome to degrade endocytosed proteins. Overexpression of mutant C-terminally truncated CHMP2B proteins produces an enlarged endosomal phenotype in PC12 and human neuroblastoma cells, which is likely to be due to a dominant-negative effect on endosomal function. Disruption of normal endosomal trafficking is likely to affect the transport of neuronal growth factors and autophagic clearance of proteins, both of which could contribute to neurodegeneration in frontotemporal dementia.
Biochemical Society Transactions 03/2009; 37(Pt 1):208-12. · 3.71 Impact Factor
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Julie van der Zee, Hazel Urwin,
Sebastiaan Engelborghs,
Marc Bruyland,
Rik Vandenberghe,
Bart Dermaut,
Tim De Pooter,
Karin Peeters,
Patrick Santens,
Peter P De Deyn,
Elizabeth M Fisher,
John Collinge,
Adrian M Isaacs,
Christine Van Broeckhoven
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ABSTRACT: The charged multivesicular body protein 2B gene (CHMP2B) was recently associated with frontotemporal lobar degeneration (FTLD) linked to chromosome 3 in a Danish FTLD family (FTD-3). In this family, a mutation in the acceptor splice site of exon 6 produced two aberrant transcripts predicting two C-truncated CHMP2B proteins due to a read through of intron 5 (p.Met178ValfsX2) and a cryptic splicing event within exon 6 (p.Met178LeufsX30). Extensive mutation analysis of CHMP2B in Belgian patients (N = 146) identified one nonsense mutation in exon 5 (c.493C>T) in a familial FTLD patient, predicting a C-truncated protein p.Gln165X analogous to the Danish mutant proteins. Overexpression of Belgian p.Gln165X in human neuroblastoma SK-N-SH cells showed the formation of large, aberrant endosomal structures that were highly similar to those observed for Danish p.Met178ValfsX2. Together, these data suggest that C-truncating mutations in CHMP2B might underlie the pathogenic mechanism in FTLD by disturbing endosome function. We also describe a missense mutation in exon 5 of CHMP2B (p.Asn143Ser) in a familial patient with cortical basal degeneration. However, the pathogenic character of this mutation remains elusive.
Human Molecular Genetics 01/2008; 17(2):313-22. · 7.64 Impact Factor
