Analyses of the nuclear protein that aggregates in brains of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration

TAR DNA结合蛋白Mr 43 kDa（TDP-43）是肌萎缩侧索硬化（ALS）和额颞叶变性（FTLD-TDP）中tau蛋白阴性和泛素阳性包涵体的主要成分。同时TDP-43病理学已在多种其他神经退行性疾病如阿尔茨海默病中报道，形成一组TDP-43蛋白质病。积累的TDP-43的特征在于磷酸化和片段化。磷酸化TDP-43的C-末端片段的免疫印迹模式与FTLD-TDP的病理亚型之间存在密切关系。这些结果表明，积累的TDP-43的蛋白水解加工可能在病理过程中发挥重要作用。在培养的细胞中，转染的TDP-43的C-末端片段比全长TDP-43更容易形成聚集体。了解TDP-43的磷酸化和截短以及聚集体形成的机制对于阐明TDP-43蛋白病的发病机制和开发有用的治疗方法可能是至关重要的。

TAR DNA-binding protein of M_r 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics.