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Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease

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Abstract

Neuronal intermediate filament inclusion disease (NIFID) is an uncommon neurodegenerative condition that typically presents as early-onset, sporadic frontotemporal dementia (FTD), associated with a pyramidal and/or extrapyramidal movement disorder. The neuropathology is characterized by frontotemporal lobar degeneration with neuronal inclusions that are immunoreactive for all class IV intermediate filaments (IF), light, medium and heavy neurofilament subunits and α-internexin. However, not all the inclusions in NIFID are IF-positive and the primary molecular defect remains uncertain. Mutations in the gene encoding the fused in sarcoma (FUS) protein have recently been identified as a cause of familial amyotrophic lateral sclerosis (ALS). Because of the recognized clinical, genetic and pathological overlap between FTD and ALS, we investigated the possible role of FUS in NIFID. We found abnormal intracellular accumulation of FUS to be a consistent feature of our NIFID cases (n = 5). More neuronal inclusions were labeled using FUS immunohistochemistry than for IF. Several types of inclusions were consistently FUS-positive but IF-negative, including neuronal intranuclear inclusions and glial cytoplasmic inclusions. Double-label immunofluorescence confirmed that many cells had only FUS-positive inclusions and that all cells with IF-positive inclusions also contained pathological FUS. No mutation in the FUS gene was identified in a single case with DNA available. These findings suggest that FUS may play an important role in the pathogenesis of NIFID.

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Acknowledgments

We thank Margaret Luk, Mareike Schroff and Mirjam Lutz for their excellent technical assistance. This work was supported by grants from Canadian Institutes of Health Research (grant number 74580, IM); the Pacific Alzheimer Research Foundation (IM); the Deutsche Forschungsgemeinschaft (SFB 596, MN); the Stavros-Niarchos Foundation (MN); the Synapsis Foundation (MN); the German Brain Bank “BrainNet” (HK) and the National Institute of Health (grant number P50 AG16574, RR).

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Authors and Affiliations

  1. Institute of Neuropathology, University Hospital of Zürich, Zurich, Switzerland

    Manuela Neumann

  2. Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany

    Sigrun Roeber & Hans A. Kretzschmar

  3. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA

    Rosa Rademakers & Matt Baker

  4. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

    Ian R. A. Mackenzie

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  1. Manuela Neumann
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  2. Sigrun Roeber
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  6. Ian R. A. Mackenzie
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Correspondence to Ian R. A. Mackenzie.

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Neumann, M., Roeber, S., Kretzschmar, H.A. et al. Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118, 605–616 (2009). https://doi.org/10.1007/s00401-009-0581-5

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