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

IRA Mackenzie, EH Bigio, PG Ince… - Annals of Neurology …, 2007 - Wiley Online Library
IRA Mackenzie, EH Bigio, PG Ince, F Geser, M Neumann, NJ Cairns, LK Kwong, MS Forman…
Annals of Neurology: Official Journal of the American Neurological …, 2007Wiley Online Library
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 …
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 dismutase1 (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), SOD1–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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