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Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations

  1. Ian R. A. Mackenzie MD1,*,
  2. Eileen H. Bigio MD2,
  3. Paul G. Ince MD3,
  4. Felix Geser MD4,13,
  5. Manuela Neumann MD5,
  6. Nigel J. Cairns PhD6,
  7. Linda K. Kwong PhD4,13,
  8. Mark S. Forman MD, PhD4,13,
  9. John Ravits MD7,
  10. Heather Stewart PhD8,
  11. Andrew Eisen MD8,
  12. Leo McClusky MD, MBE9,
  13. Hans A. Kretzschmar MD5,
  14. Camelia M. Monoranu MD10,
  15. J. Robin Highley PhD3,
  16. Janine Kirby PhD11,
  17. Teepu Siddique MD12,
  18. Pamela J. Shaw MD11,
  19. Virginia M-Y. Lee PhD, MBA4,13,
  20. John Q. Trojanowski MD, PhD4,13

Article first published online: 27 APR 2007

DOI: 10.1002/ana.21147

Issue

Annals of Neurology

Annals of Neurology

Volume 61, Issue 5, pages 427–434, May 2007

Additional Information

How to Cite

Mackenzie, I. R. A., Bigio, E. H., Ince, P. G., Geser, F., Neumann, M., Cairns, N. J., Kwong, L. K., Forman, M. S., Ravits, J., Stewart, H., Eisen, A., McClusky, L., Kretzschmar, H. A., Monoranu, C. M., Highley, J. R., Kirby, J., Siddique, T., Shaw, P. J., Lee, V. M.-Y. and Trojanowski, J. Q. (2007), Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol., 61: 427–434. doi: 10.1002/ana.21147

Author Information

  1. 1

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

  2. 2

    Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL

  3. 3

    Academic Unit of Pathology, Sheffield University Medical School, Sheffield, United Kingdom

  4. 4

    Center for Neurodegenerative Disease Research, Alzheimer's Disease Core Center, Philadelphia, PA

  5. 5

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

  6. 6

    Departments of Neurology and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO

  7. 7

    Neurogenomics Laboratory, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA

  8. 8

    Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada

  9. 9

    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA

  10. 10

    Department of Neuropathology, University of Wurzburg, Wurzburg, Germany

  11. 11

    Academic Unit of Neurology, Sheffield University Medical School, Sheffield, United Kingdom

  12. 12

    Division of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, IL

  13. 13

    Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

*Department of Pathology, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, British Columbia, Canada, V5Z 1M9

Publication History

  1. Issue published online: 27 APR 2007
  2. Article first published online: 27 APR 2007
  3. Manuscript Revised: 13 MAR 2007
  4. Manuscript Accepted: 13 MAR 2007
  5. Manuscript Received: 16 FEB 2007

Funded by

  • Canadian Institutes of Health Research. Grant Number: 74580
  • NIH (National Institute on Aging). Grant Numbers: P30 AG-10124, P01 AG-17586, P50 P50-AG05681, U01 AG-16976, AG-13854
  • German Federal Ministry of Education and Research. Grant Number: 01G10505
  • Wellcome Trust
  • UK Medical Research Council. Grant Number: G0301152

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Abstract

Objective

Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations.

Methods

Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1–negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group.

Results

All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations.

Interpretation

These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS. Ann Neurol 2007;61:427–434

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