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Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation

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Abstract

Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions of the associated neuropathology are few and largely restricted to individual case reports. To better define the neuropathology associated with FUS mutations, we have undertaken a detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial cases, with both juvenile and adult onset, and with four different FUS mutations. We found significant pathological heterogeneity among our cases, with two distinct patterns that correlated with the disease severity and the specific mutation. Frequent basophilic inclusions and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a consistent feature of our early-onset cases, including two with the p.P525L mutation. In contrast, our late-onset cases that included two with the p.R521C mutation had tangle-like NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed significant differences and suggests that FUS mutations are associated with a distinct pathobiology.

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Notes

  1. We have found that newer batches of Sigma anti-FUS, obtained following completion of this study, provide similar results when used at concentrations of 1:500–1:2,000.

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Acknowledgments

We thank Margaret Luk and Mareike Schroff for their excellent technical assistance. This work was supported by grants from the Canadian Institutes of Health Research (Grant Number 74580, IM), the Pacific Alzheimer Research Foundation (IM), the NIHR Oxford Biomedical Research Centre (OA), the NIH/NIA R01 AG26251 (RR), the ALS Association (RR), the Swiss National Science Foundation (Grant Number 31003A-132864, MN), the Stavros-Niarchos Foundation (MN) and the Synapsis Foundation (MN).

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Authors and Affiliations

  1. Department of Pathology, University of British Columbia and Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

    Ian R. A. Mackenzie

  2. Department of Neuropathology, John Radcliffe Hospital, Oxford, UK

    Olaf Ansorge

  3. Department of Clinical Neurological Sciences, London Health Sciences Centre, London, ON, Canada

    Michael Strong

  4. Department of Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Juan Bilbao

  5. Division of Neurology, University of Toronto, Toronto, ON, Canada

    Lorne Zinman

  6. Department of Pathology, London Health Sciences Centre, London, ON, Canada

    Lee-Cyn Ang

  7. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Matt Baker & Rosa Rademakers

  8. Division of Neurology, University of British Columbia, Vancouver, BC, Canada

    Heather Stewart & Andrew Eisen

  9. Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

    Manuela Neumann

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  1. Ian R. A. Mackenzie
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  2. Olaf Ansorge
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Correspondence to Ian R. A. Mackenzie.

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Mackenzie, I.R.A., Ansorge, O., Strong, M. et al. Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol 122, 87–98 (2011). https://doi.org/10.1007/s00401-011-0838-7

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  • DOI: https://doi.org/10.1007/s00401-011-0838-7

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