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

43 kDa TAR DNA结合蛋白(TDP-43)是肌萎缩侧索硬化症(ALS)和额颞叶退行性变(FTLD-TDP)的主要成分。在阿尔茨海默病等多种其他神经退行性疾病中也有TDP-43的病理报道，形成了一组TDP-43蛋白病。累积的TDP-43以磷酸化和碎裂为特征。FTLD-TDP的病理亚型与磷酸化TDP-43的C末端片段的免疫印迹模式密切相关。这些结果提示，TDP-43积聚的蛋白降解过程可能在病理过程中起重要作用。在培养细胞中，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的磷酸化和截断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至关重要。

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.