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彻底切断 MeCP2 挽救了类似雷特综合征的神经缺陷

Rebekah Tillotson¹, Jim Selfridge¹, Martha V Koerner¹

¹The Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK.

|October 12, 2017

概括

在MECP2基因的突变导致雷特综合征. 然而,只有含有DNA和共抑制剂结合域的MeCP2蛋白质可以防止神经症状,这表明它具有治疗潜力.

科学领域:

神经科学
遗传学
表观遗传学

背景情况:

雷特综合征是一种由X结合MECP2基因突变引起的神经疾病.
MeCP2 (甲基-CpG结合蛋白2) 是神经元功能至关重要的表观遗传阅读器,与许多蛋白质相互作用.
雷特综合征突变聚集在关键的相互作用部位,这表明MeCP2的功能作用集中在其中.

研究的目的:

测试MeCP2的主要功能是将DNA与NCoR/SMRT复合体联系起来.
调查MeCP2的DNA和联合抑制剂结合域的功能性.

主要方法:

产生表达缺少N和C终端区域的截断MeCP2蛋白质的小鼠.
在被修改MeCP2的小鼠中评估表型正常性和生存率.
利用基因激活和病毒介导的传递,在MeCP2缺乏的小鼠中引入最小的MeCP2.

主要成果:

表达截断的MeCP2 (缺少N和C末端区域) 的小鼠在表型上接近正常.
微小的MeCP2 (缺乏中心域) 的小鼠在轻微的症状下存活了一年多.
在MeCP2缺乏的小鼠中,最小的MeCP2表达阻止或逆转神经症状.

结论:

MeCP2的DNA和联合抑制剂结合域足以预防类似雷特综合征的缺陷.
这些最小的功能域可能对雷特综合征具有治疗效用.
尽管有进化保护,但MeCP2的核心功能似乎是将DNA与共抑制剂联系起来.

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