Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations
Article first published online: 27 APR 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 61, Issue 5, pages 427–434, May 2007
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
- Issue published online: 27 APR 2007
- Article first published online: 27 APR 2007
- Manuscript Revised: 13 MAR 2007
- Manuscript Accepted: 13 MAR 2007
- Manuscript Received: 16 FEB 2007
- 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
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.
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.
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.
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