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首页> 外文期刊>Neuropathology: official journal of the Japanese Society of Neuropathology >Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy.
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Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy.

机译：ALS，FTLD和其他神经退行性疾病以及TDP-43蛋白病的细胞模型中的TDP-43磷酸化和裂解。

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Transactivation response (TAR) DNA-binding protein of Mr 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. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. 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.
机译：Mr 43 kDa（TDP-43）的反式激活（TAR）DNA结合蛋白是tau阴性和泛素阳性包涵体的主要成分，其特征是肌萎缩性侧索硬化症（ALS）和额颞叶变性，现在称为FTLD-TDP。已经在多种其他神经退行性疾病例如阿尔茨海默氏病中报告了同时的TDP-43病理学，形成了一组TDP-43蛋白病。积累的TDP-43的特征在于磷酸化和片段化。 FTLD-TDP的病理亚型与磷酸化的TDP-43的C端片段的免疫印迹模式密切相关。这些结果表明累积的TDP-43的蛋白水解过程可能在病理过程中发挥重要作用。在培养细胞中，与全长TDP-43相比，转染的TDP-43的C端片段更易于形成聚集体。将携带家族性和散发性ALS病例的TDP-43基因的致病性突变的TDP-43的C端片段转染到细胞中，可增强聚集体的形成。此外，我们发现在这些细胞模型中，亚甲基蓝和双美本可以抑制TDP-43的聚集。了解TDP-43磷酸化和截短的机制以及聚集体的形成对于阐明TDP-43蛋白病的发病机理和开发有用的治疗方法可能至关重要。

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