• Ian R A Mackenzie, Eileen H Bigio, Paul G Ince, Felix Geser, Manuela Neumann, Nigel J Cairns, Linda K Kwong, Mark S Forman, John Ravits, Heather Stewart, Andrew Eisen, Leo McClusky, Hans A Kretzschmar, Camelia M Monoranu, J Robin Highley, Janine Kirby, Teepu Siddique, Pamela J Shaw, Virginia M-Y Lee, and John Q Trojanowski.
• Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. ian.mackenzie@vch.ca
• Ann. Neurol. 2007 May 1; 61 (5): 427-34.

ObjectiveAmyotrophic 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.MethodsUbiquitin 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.ResultsAll 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.InterpretationThese 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.

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