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

Acta Neuropathol. 2010 Jul;120(1):33-41. doi: 10.1007/s00401-010-0698-6. Epub 2010 May 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • DNA-Binding Proteins / metabolism
  • Dyskinesias / epidemiology
  • Female
  • Frontal Lobe / metabolism
  • Frontotemporal Lobar Degeneration / epidemiology*
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / metabolism*
  • Hippocampus / metabolism
  • Humans
  • Male
  • Mental Disorders / epidemiology
  • Middle Aged
  • Mutation
  • Prevalence
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism*
  • Sequence Analysis, DNA
  • tau Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • MAPT protein, human
  • RNA-Binding Protein FUS
  • tau Proteins