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Pathological TDP‐43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations
Author(s) -
Mackenzie Ian R. A.,
Bigio Eileen H.,
Ince Paul G.,
Geser Felix,
Neumann Manuela,
Cairns Nigel J.,
Kwong Linda K.,
Forman Mark S.,
Ravits John,
Stewart Heather,
Eisen Andrew,
McClusky Leo,
Kretzschmar Hans A.,
Monoranu Camelia M.,
Highley J. Robin,
Kirby Janine,
Siddique Teepu,
Shaw Pamela J.,
Lee Virginia MY.,
Trojanowski John Q.
Publication year - 2007
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21147
Subject(s) - amyotrophic lateral sclerosis , sod1 , pathological , pathology , pathogenesis , mutation , medicine , motor neuron , dementia , biology , genetics , disease , gene
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