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 M-Y, Trojanowski John Q
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Ann Neurol. 2007 May;61(5):427-34. doi: 10.1002/ana.21147.
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.
肌萎缩侧索硬化症（ALS）是一种常见的致命性运动神经元疾病，目前尚无有效治疗方法。约10%的病例为家族性ALS（FALS），最常见的基因异常是超氧化物歧化酶-1（SOD1）突变。过去十年中，大多数ALS研究都集中在突变型SOD1的神经毒性上，这一认知为治疗策略提供了方向。我们最近发现TDP-43是散发性ALS的主要病理蛋白。在本研究中，我们对更多系列的ALS病例（n = 111）进行了TDP-43研究，包括有和没有SOD1突变的家族性病例。
对散发性ALS（n = 59）、伴有SOD1突变的ALS（n = 15）、SOD-1阴性FALS（n = 11）以及伴有痴呆的ALS（n = 26）的尸检组织进行泛素和TDP-43免疫组织化学检测。对每组中的代表性病例进行生化分析。
所有散发性ALS、伴有痴呆的ALS以及SOD1阴性FALS病例均有神经元和胶质细胞包涵体，对泛素和TDP-43均呈免疫反应性。伴有SOD1突变的病例有泛素阳性的神经元包涵体；然而，没有病例对TDP-43呈免疫反应性。对散发性ALS和SOD1阴性FALS尸检组织的生化分析显示存在TDP-43的病理形式，而伴有SOD1突变的病例中不存在这种形式。
这些发现表明病理性TDP-43参与散发性ALS的发病机制。相比之下，伴有SOD1突变的病例中不存在病理性TDP-43，这意味着这些病例中的运动神经元变性可能由不同机制导致，并且伴有SOD1突变的病例可能不是散发性ALS的家族对应类型。
