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α-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

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Abstract

Abnormal neuronal aggregates of α-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. α-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, α-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal dementias, motor neuron disease, α-synucleinopathies, tauopathies, and normal aged control brains. Our results indicate that class IV IF proteins are present within the pleomorphic inclusions of all cases of NIFID. Small subsets of abnormal neuronal inclusions in Alzheimer’s disease, Lewy body diseases, and motor neuron disease also contain epitopes of α-internexin. Thus, α-internexin is a major component of the neuronal inclusions in NIFID and a relatively minor component of inclusions in other neurodegenerative diseases. The discovery of α-internexin in neuronal cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological filamentous neuronal inclusions.

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Acknowledgements

We thank Dr. D. Munoz for tissue samples and the staff of the Center for Neurodegenerative Disease Research of the University of Pennsylvania for technical support, and we thank the families of patients whose generosity made this research possible. Support for this work was provided by grants from the National Institute on Aging of the National Institutes of Health (AG-09215, AG-10124, AG-17586 to V.M.-Y.L. and J.Q.T., and AG-10130 and ES12068 to M.G.), and from the Wellcome Trust (GR066166AIA) to N.J.C. V.M.-Y.L. is the John H. Ware, 3rd Professor of Alzheimer’s Research and J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr. M.D., Professor of Geriatric Medicine and Gerontology.

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Authors and Affiliations

  1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney 3, HUP, 3600 Spruce Street, Philadelphia, PA 19104-4283, USA

    Nigel J. Cairns, Kunihiro Uryu, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Neuropathology, Northwestern University Medical School, Chicago, Illinois, USA

    Eileen H. Bigio

  3. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada

    Ian R. A. Mackenzie

  4. Department of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia, USA

    Marla Gearing

  5. Laboratoire de Neuropathologie, Hôpital de la Salpêtrière, Paris, France

    Charles Duyckaerts

  6. Department of Pathology, Gunma University School of Medicine, Maebashi, Japan

    Hideaki Yokoo & Yoichi Nakazato

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

    Evelyn Jaros & Robert H. Perry

  8. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Steven E. Arnold

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  1. Nigel J. Cairns
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  2. Kunihiro Uryu
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  3. Eileen H. Bigio
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  7. Hideaki Yokoo
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  9. Evelyn Jaros
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  10. Robert H. Perry
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  11. Steven E. Arnold
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  12. Virginia M.-Y. Lee
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  13. John Q. Trojanowski
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Correspondence to Nigel J. Cairns.

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Cairns, N.J., Uryu, K., Bigio, E.H. et al. α-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases. Acta Neuropathol 108, 213–223 (2004). https://doi.org/10.1007/s00401-004-0882-7

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  • DOI: https://doi.org/10.1007/s00401-004-0882-7

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