本文的研究显示,ddx6除了发挥其正常的功能外,其还会对肌营养不良症患者机体细胞中的毒性rna聚集物具有直接的影响
如今ddx6用于治疗肌营养不良症的机制尚不清楚,然而本文的研究结果对于理解肌营养不良症发病的机制非常重要,不同类型细胞中酶类水平的天然差别或可帮助解释疾病发展过程中的组织特异性差异(生物谷bioon.com)
研究者通过研究表明,肌营养不良症细胞中ddx6水平的人为升高会降低细胞中rna聚合物的数量,但当ddx6被移除后,rna聚合物的水平就会猛增;ddx6属于解螺旋酶家族中的一种,解螺旋酶可以改变rna的结构并且会调节蛋白质和rna结合的能力;通过对人类细胞中ddx6的纯化,研究人员成功地实现了该肌强直性肌病酶在细胞外的反应,同时也改变了毒性rna的结构
pmid:
doi:10.1093/nar/gku352
myotonic dystrophy type 1 (dm1) is caused by cug triplet expansions in the 3′ utr of dystrophia myotonica protein kinase (dmpk) messenger ribonucleic acid (mrna). the etiology of this multi-systemic disease involves pre-mrna splicing defects elicited by the ability of神经性肌强直 the cug-expanded mrna to ‘sponge’ splicing factors of the muscleblind family. although nuclear aggregation of cug-containing mrnps in distinct foci is a hallmark of dm1, the mechanisms of their homeostasis have not been completely elucidated. here we show that a dead-box helicase, ddx6, interacts wit获得性神经性肌强直h cug triplet-repeat mrna in primary fibroblasts from dm1 patients and with cug–rna in vitro. ddx6 overexpression relieves dm1 mis-splicing, and causes a significant reduction in nuclear dmpk-mrna foci. conversely, knockdown of endogenous ddx6 leads to a significant increase in dmpk-mrna foci count and 震颤性肌强直to increased sequestration of mbnl1 in the nucleus. while the level of cug-expanded mrna is unaffected by increased ddx6 expression, the mrna re-localizes to the cytoplasm and its interaction partner mbnl1 becomes dispersed and also partially re-localized to the cytoplasm. finally, we show that ddx6 unw先天性肌强直inds cug-repeat duplexes in vitro in an adenosinetriphosphate-dependent manner, suggesting that ddx6 can remodel and release nuclear dmpk messenger ribonucleoprotein foci, leading to normalization of pathogenic alternative splicing events.
ddx6 regulates sequestered nuclear cug-expanded dmpk-mrna in dy神经性肌强直strophia myotonica type 1
pmc:
olof j. pettersson1, lars aagaard1, diana andrejeva2, rune thomsen2, thomas g. jensen1 and christian k. damgaard2,*
2014年5月6日 讯 /生物谷bioon/ --成年人中常见的肌营养不良症是营养不良性肌强直1型(dm1),大约8000人中就会有1人是dm1疾病,近日,刊登在国际杂志nucleic acids research上的一篇研究论文中,来自奥尔胡斯大学的科学家通过研究在肌营养不良症患者的机体细胞中发现了一种新型的名为ddx6的酶类,这对于研究者开发新型治疗肌营养肌强直不良症的疗法非常关键
在肌营养不良症患者机体细胞中,酶类ddx6会清除毒性聚合物并且释放细胞中的盲肌(muscleblind),这就意味着ddx6可以发挥正常的功能,ddx6在许多不同类型的细胞中都存在,在那些细胞中其扮演着重要角色
