TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions
TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions
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DOI：
10.2353/ajpath.2007.070182
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发表时间：
2007-07-01
影响因子：
6
通讯作者：
Mackenzie, Ian R. A.
中科院分区：
文献类型：
--
作者：
Cairns, Nigel J.;Neumann, Manuela;Mackenzie, Ian R. A.
TAR DNA结合蛋白43（TDP - 43）是散发性和家族性额颞叶变性伴泛素阳性、tau阴性包涵体（FTLD - U）（伴或不伴运动神经元疾病（MND））的主要病理蛋白。因此，TDP - 43定义了一类新的神经退行性疾病，称为TDP - 43蛋白病。我们对193例伴或不伴MND的家族性和散发性FTLD进行了泛素和TDP - 43免疫组织化学研究。对选定的病例进行了免疫电子显微镜检查和生物化学分析。临床定义的额颞叶痴呆（FTD）包括四组：1）伴有颗粒蛋白前体突变的家族性FTD（n = 36）、含缬酪肽蛋白突变（n = 5）、带电多泡体蛋白2B突变（n = 4）以及与9p染色体相关的（n = 7）；2）基因关联未知的家族性FTD病例（n = 29）；3）散发性FTD（n = 72）；4）伴MND的家族性和散发性FTD（n = 40）。我们的研究证实，TDP - 43蛋白病的范畴包括大多数伴或不伴MND的散发性和家族性FTLD - U病例，并将这一疾病范畴扩展到包括已报道的与9p染色体相关的FTD家族，但不包括带电多泡体蛋白2B突变的FTD。因此，尽管FTLD - U在临床、遗传和神经病理学方面存在显著的异质性，但TDP - 43是这些疾病中很大一部分的常见病理基础，从而表明TDP - 43参与了FTLD发病机制的新的统一机制。
TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and Sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FMs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and fainthal FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FM with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.