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FUS Immunogold Labeling TEM Analysis of the Neuronal Cytoplasmic Inclusions of Neuronal Intermediate Filament Inclusion Disease: A Frontotemporal Lobar Degeneration with FUS Proteinopathy

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Abstract

Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three frontotemporal lobar degeneration entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of α-internexin and neurofilament proteins. Herein, we have shown that: (1) FUS becomes relatively insoluble in NIFID and there are no apparent posttranslational modifications, (2) there are no pathogenic abnormalities in the FUS gene in NIFID, and (3) immunoelectron microscopy demonstrates the fine structural localization of FUS in NIFID which has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the “loosely aggregated cytoplasmic inclusions,” 81% of which had moderate or high levels of FUS immunoreactivity. Much rarer “compact cytoplasmic inclusions” and “tangled twine ball inclusions” were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus, FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations.

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Acknowledgments

A preliminary report of these data was presented at the 7th International Conference on Frontotemporal Dementias 2010, Indianapolis, IN, USA. We thank the families of patients whose generosity made this research possible. We acknowledge the staff of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center Neuropathology Laboratory and the Departments of Neurology and Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA, for the technical assistance. Support for this work was provided by a grant from the Jean Shanks Foundation to TP and grants from the Wellcome Trust, UK, (GR066166AIA) to JRT and NJC, and the National Institute on Aging of the National Institutes of Health (P50 AG05681 and P01 AG03991) and the Friedman Award to NJC.

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Authors and Affiliations

  1. Electron Microscope Division, Sussex Centre for Advanced Microscopy, John Maynard-Smith Building, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, East Sussex, UK

    Tristan Page & Julian R. Thorpe

  2. Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI, USA

    Michael A. Gitcho

  3. Department of Clinical Biochemistry, Royal Berkshire NHS Foundation Trust, Reading, Berkshire, UK

    Sabrina Mosaheb

  4. Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    Deborah Carter, Sumi Chakraverty, Alison M. Goate & Nigel J. Cairns

  5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Deborah Carter & Nigel J. Cairns

  6. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

    Sumi Chakraverty & Alison M. Goate

  7. Department of Neuropathology, Newcastle General Hospital, Newcastle-upon-Tyne, UK

    Robert H. Perry

  8. Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Eileen H. Bigio

  9. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Eileen H. Bigio

  10. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Marla Gearing

  11. Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA

    Marla Gearing

  12. Institut de Neuropatologia, Idibell-Hospital Universityari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Spain

    Isidre Ferrer

  13. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Alison M. Goate & Nigel J. Cairns

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  1. Tristan Page
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Correspondence to Julian R. Thorpe.

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Tristan Page and Michael A. Gitcho contributed equally to this work.

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Page, T., Gitcho, M.A., Mosaheb, S. et al. FUS Immunogold Labeling TEM Analysis of the Neuronal Cytoplasmic Inclusions of Neuronal Intermediate Filament Inclusion Disease: A Frontotemporal Lobar Degeneration with FUS Proteinopathy. J Mol Neurosci 45, 409–421 (2011). https://doi.org/10.1007/s12031-011-9549-8

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