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FUS-Immunoreactive Intranuclear Inclusions in Neurodegenerative Disease

Authors

  • John Woulfe,

    Corresponding author
    1. Cancer Therapeutics Group, Ottawa Hospital Research Institute.
    2. Department of Pathology and Laboratory Medicine and
      John Woulfe, MD PhD, Department of Pathology, The Ottawa Hospital, Civic Campus, 1053 Carling Ave., Ottawa, Ontario, Canada, K1Y 4E9 (E-mail: jwoulfe@ottawahospital.on.ca)
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  • Douglas A. Gray,

    1. Cancer Therapeutics Group, Ottawa Hospital Research Institute.
    2. Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa.
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  • Ian R.A. Mackenzie

    1. Department of Pathology, University of British Columbia, Vancouver, Canada.
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John Woulfe, MD PhD, Department of Pathology, The Ottawa Hospital, Civic Campus, 1053 Carling Ave., Ottawa, Ontario, Canada, K1Y 4E9 (E-mail: jwoulfe@ottawahospital.on.ca)

Abstract

Neuronal intranuclear inclusions (NIIs) are a histopathological hallmark of several neurodegenerative disorders. However, the role played by NIIs in neurodegenerative pathogenesis remains enigmatic. Defining their molecular composition represents an important step in understanding the pathophysiology of these disorders. Recently, a nuclear protein, “fused-in-sarcoma” (FUS) was identified as the pathological protein in two forms of frontotemporal lobar degeneration (FTLD-IF, formerly known as neuronal intermediate filament inclusion disease, and FTLD-UPS, formerly known as atypical FTLD-U), both of which are characterized by the presence of NII. The objective of the present study was to determine the range of neurodegenerative disorders characterized by FUS-positive NIIs. Immunostaining for FUS revealed intense reactivity of NIIs in FTLD-IF and FTLD-UPS as well as in Huntington's disease, spinocerebellar ataxias 1 and 3, and neuronal intranuclear inclusion body disease. In contrast, there was no FUS staining of NIIs in inherited forms of FTLD-TDP caused by GRN and VCP mutations, fragile-X-associated tremor ataxia syndrome, or oculopharyngeal muscular dystrophy. In a cell culture model of Huntington's disease, NIIs were intensely FUS-positive. NII-bearing cells displayed loss of the normal diffuse nuclear pattern of FUS staining. This suggests that sequestration of nuclear FUS by NIIs may interfere with its normal nuclear localization.

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