Akiyama Haruhiko, Hasegawa Masato
Tokyo Metropolitan Institute of Medical Science, Dementia Research Project.
Brain Nerve. 2013 Dec;65(12):1477-89.
TAR DNA-binding protein 43 (TDP-43) is a member of the heterogeneous nuclear ribonucleoprotein family, a group of proteins involved in pre-mRNA splicing, RNA stability, transport, and metabolism. TDP-43 was identified as the major component of pathological protein aggregates present in a subset of frontotemporal lobar degeneration (FTLD), which is now referred to as FTLD-TDP. TDP-43 is also deposited in the sporadic form of amyotrophic lateral sclerosis (ALS) as well as in familial ALS with mutations in the gene for TDP-43. Based on histopathology, the accumulation of TDP-43 in the brain cortex is classified into 4 types, type A through D, depending on the forms of TDP-43 accumulation in the cerebral cortex. Type A pathology is frequently observed in frontotemporal dementia and progressive non-fluent aphasia. Type B pathology occurs in FTLD with ALS and ALS with lesions that extend to the cerebral cortex. Type C pathology is associated with semantic dementia. In FTLD and ALS, TDP-43 forms insoluble aggregates and gets phosphorylated, ubiquitinated, and fragmented. The fragment patterns on immunoblot of brain homogenates correspond to each histopathological type, indicating their relevance to the pathogenesis of TDP-43 proteinopathy.
TAR DNA结合蛋白43（TDP - 43）是不均一核核糖核蛋白家族的成员，该家族的一组蛋白质参与前体mRNA剪接、RNA稳定性、运输及代谢。TDP - 43被鉴定为额颞叶痴呆（FTLD）的一个亚组中存在的病理性蛋白聚集体的主要成分，现称为FTLD - TDP。TDP - 43也以散发性肌萎缩侧索硬化（ALS）以及TDP - 43基因发生突变的家族性ALS的形式沉积。基于组织病理学，根据TDP - 43在大脑皮层的积聚形式，大脑皮层中TDP - 43的积聚分为A至D 4种类型。A型病理学常见于额颞叶痴呆和进行性非流畅性失语。B型病理学发生于合并ALS的FTLD以及病变延伸至大脑皮层的ALS。C型病理学与语义性痴呆相关。在FTLD和ALS中，TDP - 43形成不溶性聚集体并发生磷酸化、泛素化及片段化。脑匀浆免疫印迹上的片段模式与每种组织病理学类型相对应，表明它们与TDP - 43蛋白病的发病机制相关。
