Mackenzie Ian R A, Rademakers Rosa
Department of Pathology, Vancouver General Hospital, British Columbia, Canada.
Curr Opin Neurol. 2008 Dec;21(6):693-700. doi: 10.1097/WCO.0b013e3283168d1d.
We examine current evidence that the transactive response DNA-binding protein (TDP-43) plays a pathogenic role in both amyotrophic lateral sclerosis and frontotemporal dementia.
TDP-43 was recently identified as the major pathological protein in sporadic amyotrophic lateral sclerosis and in the most common pathological subtype of frontotemporal dementia, frontotemporal lobar degeneration with ubiquitinated inclusions. In these conditions, abnormal C-terminal fragments of TDP-43 are ubiquitinated, hyperphosphorylated and accumulate as cellular inclusions in neurons and glia. Cells with inclusions show absence of the normal nuclear TDP-43 localization. Recently, missense mutations in the gene encoding TDP-43 have been identified in patients with sporadic and familial amyotrophic lateral sclerosis.
The recent discovery of pathological TDP-43 in both amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions confirms that these are closely related conditions within a new biochemical class of neurodegenerative disease, the TDP-43 proteinopathies.
我们研究了目前有关反式激活反应DNA结合蛋白（TDP - 43）在肌萎缩侧索硬化症和额颞叶痴呆中起致病作用的证据。
TDP - 43最近被确定为散发性肌萎缩侧索硬化症以及额颞叶痴呆最常见病理亚型——伴有泛素化包涵体的额颞叶变性中的主要病理蛋白。在这些病症中，TDP - 43的异常C末端片段被泛素化、高度磷酸化，并作为细胞内包涵体在神经元和神经胶质细胞中积聚。含有包涵体的细胞显示正常的核TDP - 43定位缺失。最近，在散发性和家族性肌萎缩侧索硬化症患者中发现了编码TDP - 43的基因中的错义突变。
最近在肌萎缩侧索硬化症和伴有泛素化包涵体的额颞叶变性中发现病理性TDP - 43，证实了这些病症是神经退行性疾病新生化类别——TDP - 43蛋白病中密切相关的病症。
