智力障碍(智障)又称智力低下或精神发育迟滞,是指18岁以前出现的认知功能低下(智商&70)和社会适应能力不足,是一组严重危害儿童青少年身心健康的神经精神疾病。脆性X是世界范围内最常见的遗传性智力低下疾病,其发病率约在每4000个男性和8000个女性中有一人发病。脆性X不仅给患儿和家庭造成终生的痛苦,同时也为家庭和社会带来了沉重的经济负担。
中科院遗传与发育生物学研究所张永清组和湖北大学的金珊教授研究组合作研究发现,脆性X蛋白FMRP调控微管的网络形成。当缺失dfmr1时,细胞核周围的微管变得更加密集,而细胞核之间的微管密度下降,并且微管网络破坏,呈无序缠结。而当过高表达dfmr1时,细胞微管成束并相互平行。dfmr1还影响微管蛋白和乙酰化微管蛋白的表达量。研究人员利用遗传学方法筛选到dfmr1互作基因spastin。Spastin是微管剪切蛋白,它的缺失在人类可以导致临床上常见的遗传性痉挛性截瘫。研究发现,spastin突变可以抑制过高表达dfmr1产生的微管结构和表达量的变化。并且在神经系统中,dfmr1与spastin相互作用影响神经肌肉突触的形态发育。线粒体的运输依赖于微管。研究人员进一步利用免疫组化和现代活体分析技术发现,dfmr1影响轴突中线粒体的数目和运输。
这些结果为脆性X的发病机理以及治疗药物的筛选提供了新的思路和靶点。(
推荐英文摘要:
Hum.Mol.Genet. doi:10.1093/hmg/ddq431
Drosophila FMRP regulates microtubule network formation and axonal transport of mitochondria
Aiyu Yao1, Shan Jin1,2, Xinhai Li1, Zhihua Liu1, Xuehua Ma1, Jing Tang1 and Yong Q. Zhang1,*
1Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
2College of Life Sciences, Hubei University, Wuhan, Hubei 430062, China
Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the fragile X mental retardation protein FMRP. The RNA-binding FMRP represses translation of the microtubule-associated protein 1B (MAP1B) during synaptogenesis in the brain of the neonatal mouse. However, the effect of FMRP on microtubules remains unclear. Mounting evidence shows that the structure and function of FMRP are well conserved across species from Drosophila to human. From a genetic screen, we identified spastin as a dominant suppressor of rough eye caused by dfmr1 over-expression. spastin encodes a microtubule-severing protein and its mutations cause neurodegenerative hereditary spastic paraplegia. Epistatic and biochemical analysis revealed that dfmr1 acts upstream of or in parallel with spastin in multiple processes, including synapse development, locomotive behaviour and microtubule network formation. Immunostaining showed that both loss- and gain-of-function mutations of dfmr1 result in an apparently altered microtubule network. Western analysis revealed that the levels of α-tubulin and acetylated microtubules remained normal in dfmr1 mutants but increased significantly when dfmr1 was over-expressed. To examine the consequence of the aberrant microtubules in dfmr1 mutants, we analysed the microtubule-dependent mitochondrial transport and found that the number of mitochondria and the flux of mitochondrial transport are negatively regulated by dfmr1. These results demonstrate that dFMRP plays a crucial role in controlling microtubule formation and mitochondrial transport. Thus, defective microtubules and abnormal mitochondrial transport might account for, at least partially, the pathogenesis of fragile X mental retardation.