Acta Neuropathologica

, 118:617

FUS pathology in basophilic inclusion body disease

Authors

    • Division of Pathology, Department of Laboratory Medicine and Pathobiology, Room # “2-097 Cardinal Carter”, St. Michael’s HospitalUniversity of Toronto
  • Manuela Neumann
    • Institute of NeuropathologyUniversity Hospital of Zürich
  • Hirofumi Kusaka
    • Department of NeurologyKansai Medical University
  • Osamu Yokota
    • Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Kenji Ishihara
    • Department of NeurologyShowa University School of Medicine
  • Seishi Terada
    • Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Shigetoshi Kuroda
    • Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Ian R. Mackenzie
    • Department of PathologyVancouver General Hospital
Original Paper

DOI: 10.1007/s00401-009-0598-9

Cite this article as:
Munoz, D.G., Neumann, M., Kusaka, H. et al. Acta Neuropathol (2009) 118: 617. doi:10.1007/s00401-009-0598-9

Abstract

Basophilic Inclusion Body Disease (BIBD) is a tau-negative form of frontotemporal lobar degeneration (FTLD), characterized by neuronal cytoplasmic inclusions (NCI) that are visible on hematoxylin and eosin stain (HE), contain RNA, and are inconsistently ubiquitin-immunoreactive (ir). The normal nuclear expression of TDP-43 is not altered. Here we investigate whether the distribution of the structurally and functionally related protein fused in sarcoma (FUS) is altered in BIBD. Mutations in the FUS gene have recently been identified as a cause of familial amyotrophic lateral sclerosis (ALS). In addition to these familial ALS cases, FUS protein has recently been demonstrated in NCI in a subset of FTLD with ubiquitinated inclusions (atypical FTLD-U) and in neuronal intermediate filament inclusion disease (NIFID). We examined seven BIBD brains of patients with average age at onset 46 (range 29–57) and average duration of disease 8 years (range 5–12). Three cases presented with the behavioural variant of fronto-temporal dementia (FTD-bv) and one with FTD-bv combined with severe dysarthria. All four developed motor neuron disease/ALS syndrome (MND/ALS) several years later. In the other three cases, presentation was predominantly with motor symptoms, construed as MND/ALS in two, and progressive supranuclear palsy (PSP) in one. Severity of cortical degeneration varied, but all cases shared severe nigrostriatal atrophy and lower motor neuron pathology. In spared areas of cortex, FUS antibodies showed intense labelling of neuronal nuclei and weak positivity of cytoplasm, whereas, in affected areas, intense labelling of NCI was accompanied by reduction or disappearance of the normal IR pattern. The number of FUS-ir NCI was much greater than the number detected by HE or with ubiquitin or P62 immunohistochemistry. FUS-ir glial cytoplasmic inclusions (GCI) were abundant in the grey and white matter in all cases, whereas neuronal intranuclear inclusions were rare and only seen in 2/7 cases. Thus, BIBD shares with atypical FTLD-U and NIFID the presence of FUS-ir NCI and GCI, and together comprise a new biochemical category of neurodegenerative disease (FUS proteinopathies). The consistent involvement of motorneurons in BIBD indicates that the association of FTLD and MND/ALS can occur on a FUS or TDP-43 pathological substrate.

Keywords

FTLD Frontotemporal lobar degeneration FTD Frontotemporal dementia Dendritic mRNA TDP-43 Pick’s disease

Copyright information

© Springer-Verlag 2009