Brain:科学家提出治疗渐冻人症新策略

2019-04-10 佚名 中国生物技术网

4月1日,《大脑》杂志在线发表了题为《重新激活无义介导的mRNA降解通路可有效对抗C9orf72双肽重复序列的神经毒性》的研究论文。该项研究揭示了导致部分肌萎缩性侧索硬化症(ALS)的新机制,证实了激活无义介导的mRNA降解通路可以作为治疗ALS的新策略,并发现了一种现有的用于治疗哮喘的药物有可能成为治疗ALS的新药。该研究工作由中国科学院神经科学研究所、神经科学国家重点实验室徐进研究组完成。

4月1日,《大脑》杂志在线发表了题为《重新激活无义介导的mRNA降解通路可有效对抗C9orf72双肽重复序列的神经毒性》的研究论文。该项研究揭示了导致部分肌萎缩性侧索硬化症(ALS)的新机制,证实了激活无义介导的mRNA降解通路可以作为治疗ALS的新策略,并发现了一种现有的用于治疗哮喘的药物有可能成为治疗ALS的新药。该研究工作由中国科学院神经科学研究所、神经科学国家重点实验室徐进研究组完成。

ALS,俗称渐冻人症,是一种由于运动神经元进行性死亡造成的严重的神经退行性疾病。目前对ALS缺乏有效的干预治疗手段。一旦确诊,患者多在3-5年内去世,因此对ALS新药的研发有迫切需求。C9orf72的遗传学变异不仅是造成家族性ALS最常见的因素,也会导致部分散发性ALS。与多数基因突变不同,C9orf72 基因非编码区内的六碱基重复序列(HRE)是致病的主要原因。这些重复序列还可以被翻译成具有神经毒性的双肽重复序列。同时,有证据表明C9orf72和其他一些ALS致病基因可能会影响RNA代谢等共同的功能通路,但是它们造成神经毒性的具体机制尚不完全明确。

在该研究中,研究人员首先通过对ALS患者大脑组织、人源细胞进行大量生物信息学数据的分析和比对,发现C9orf72 六核苷酸重复序列可以抑制一条称为无义介导的mRNA降解(NMD)通路。然后他们在细胞、果蝇、小鼠等实验模型中运用多种方法对这一结论进行了验证,并发现了C9orf72双肽重复序列可以通过增加应激颗粒(stress granule)并减少Processing body的产生来抑制NMD这一细胞生物学机制。NMD是细胞中清除有害、错误RNA产物的一种监测及防御机制。因此,他们尝试激活NMD通路来阻碍C9orf72重复序列的神经毒性并检验NMD作为药物靶点的可能性。在细胞和果蝇模型中增加NMD通路的核心蛋白UPF1的表达可以有效阻碍C9orf72重复序列的神经毒性。此外,通过对一些潜在的NMD激活剂进行反复验证,他们发现Tranilast有稳定的激活NMD通路的特征,并可以同样对C9orf72重复序列的神经毒性起到保护作用。鉴于从1980年代开始Tranilast(曲尼斯特)就在临床中用于治疗哮喘,并有较强的安全性,也可以通过血脑屏障,这项新的研究将促进Tranilast及其他NMD激活剂作为治疗ALS创新药的动物实验及临床研究,为ALS患者带来新的希望。

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    2019-04-18 jin321

    还要很多年

    0

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    2019-04-12 nymo
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    2019-04-10 坚强007

    向挑战病魔的科研人员致敬!

    0

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