C9orf72突变致病的分子机制

Molecular Pathological Mechanisms Related with C9orf72 Mutation

C9orf72突变是导致肌萎缩侧索硬化症和额颞叶痴呆最主要的突变形式,该突变由GGGGCC长重复序列插入C9orf72基因的内含子中造成.该突变有3种致病机制:由C9orf72蛋白表达量降低造成的功能缺失、长重复序列RNA造成的细胞毒性、长重复RNA转录产物造成的细胞毒性.本文就从3个方面综合分析了该突变的分子学致病机制,从RNA和蛋白质代谢以及核仁应激三方面总结了3种致病机制之间的联系,并对该突变致病机制研究遇到的困难和未来发展方向进行了总结和预测.

GGGGCC expansion inserted in the intron of C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia.Three mechanisms are responsible for the pathological changes caused by this mutation：the reduced level of C9orf72 protein,the toxic repeat RNA transcripts,and the DRPs translated by the repeat RNA.We summarized the pathological changes induced by each of these three pathways and expounded their synergistic effect on RNA metabolism,protein metabolism and nucleolar stress.We also analyzed the obstacles we faced right now and made a prediction about the future research tendency based on that.