Kawahara Yukio
Laboratory of RNA Function, Graduate School of Medicine, Osaka University.
Rinsho Shinkeigaku. 2010 Nov;50(11):979-81. doi: 10.5692/clinicalneurol.50.979.
Recent studies have identified mutations in the genes encoding TDP-43 and FUS/TLS in patients with amyotrophic lateral sclerosis (ALS). Both TDP-43 and FUS/TLS display all the characteristics of a heterogeneous nuclear ribonucleoprotein, which regulates various aspects of RNA processing. In addition, TDP-43 is partly cleared from the nuclei of neurons containing cytoplasmic aggregates, suggesting loss of normal TDP-43 function in the nucleus, leading to defects or alterations in RNA metabolism, plays, at least in part, a causative role in the pathogenesis of ALS. TDP-43 has been reported to be involved in the Drosha complex required for the biogenesis of microRNAs. The high expression level of microRNAs and the exclusive expression of certain microRNAs in the central nervous system highlights their biological importance at all stages of neural development as well as in differentiated neurons. In addition, the altered expression of certain microRNAs has been implicated in the pathogenesis of neurodegenerative diseases. Therefore, elucidation of the role of TDP-43 in microRNA biogenesis as a component of the Drosha complex is indispensable to understanding pathophysiology of ALS. In addition, the identification of TDP-43-regulated microRNAs associated with motor neuron death is expected to further contribute to the development of novel therapeutic strategies for ALS treatment.
最近的研究已经在肌萎缩侧索硬化症（ALS）患者中鉴定出编码TDP - 43和FUS/TLS的基因突变。TDP - 43和FUS/TLS均表现出不均一核核糖核蛋白的所有特征，该蛋白调节RNA加工的各个方面。此外，TDP - 43部分地从含有细胞质聚集体的神经元细胞核中清除，这表明细胞核中正常TDP - 43功能丧失，导致RNA代谢缺陷或改变，这至少在一定程度上在ALS的发病机制中起致病作用。据报道，TDP - 43参与了微小RNA生物合成所需的Drosha复合体。微小RNA的高表达水平以及某些微小RNA在中枢神经系统中的特异性表达突出了它们在神经发育的所有阶段以及分化神经元中的生物学重要性。此外，某些微小RNA的表达改变与神经退行性疾病的发病机制有关。因此，阐明TDP - 43作为Drosha复合体的一个组成部分在微小RNA生物合成中的作用对于理解ALS的病理生理学是必不可少的。此外，鉴定与运动神经元死亡相关的TDP - 43调节的微小RNA有望进一步推动ALS治疗新策略的开发。
