Autophagy:复旦研究人员发现神经退行性疾病新靶标

2017-11-19 海北 MedSci原创

宏自噬/自噬是一种重要的细胞蛋白质质量控制过程,其可以清除细胞内有聚集倾向的蛋白质。这些蛋白质可能会引起神经退行性疾病,如亨廷顿病(HD),该病症主要是由突变的HTT / Hdh蛋白(mHTT)的细胞毒性引起的。

宏自噬/自噬是一种重要的细胞蛋白质质量控制过程,其可以清除细胞内有聚集倾向的蛋白质。这些蛋白质可能会引起神经退行性疾病,如亨廷顿病(HD),该病症主要是由突变的HTT / Hdh蛋白(mHTT)的细胞毒性引起的。因此,自噬调节剂可以调节细胞内mHTT水平,并成为HD和类似疾病潜在的药物靶标。但是,研究表明,由于一些未知的机制,HD和其他神经退行性疾病中的自噬功能通常受损。

在最近的一项研究中,复旦大学的研究人员发现了一个正反馈机制,该机制可能参与mHTT的积累和自噬功能障碍的发生。研究人员通过基因组筛选手段,鉴定出激酶基因HIPK3作为自噬的负调节因子,并且是HD细胞中mHTT水平的正调节剂。

敲低或敲除HIPK3可以通过增强HD细胞中和HD小鼠模型中的自噬水平,降低mHTT水平。有趣的是,mHTT可以正向调节HD细胞和HD小鼠脑中的HIPK3 mRNA水平,这在mHTT和HIPK3之间形成正反馈机制。这个循环潜在地抑制了自噬,造成mHTT积累和HD的疾病进展。 HIPK3对mHTT的调节依赖于其激酶活性及其已知的底物DAXX,该发现提供了潜在的HD药物靶标。

总的来说,研究人员的数据揭示了HD细胞中自噬的新型激酶调节剂,为HD和类似疾病提供了治疗切入点。


原始出处:

Yuhua Fu et al. HIPK3 modulates autophagy and HTT protein levels in neuronal and mouse models of Huntington diseaseAutophagy, 2017. DOI: http://dx.doi.org/10.1080/15548627.2017.1393130


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    2017-12-03 sunfeifeiyang

    学习

    0

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    2017-11-21 zhaojie88
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    2017-11-21 saikp

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