Astrid Authier

Publications (2)16.96 Total impact

• Source

  Available from: Christine Van Broeckhoven

  Article: FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.

  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
• Source

  Available from: Christine Van Broeckhoven

  Article: Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations.

  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