C9ORF72的重复扩张改变了神经发育
Eric Hendricks1, Alicia M Quihuis2, Shu-Ting Hung1
1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Cell reports
|August 17, 2023
概括
C9ORF72重复扩张是前性痴呆症 (FTD) 和ALS的原因,通过减少神经干细胞增殖,损害了胚胎大脑发育. 这种发育缺陷增加了晚年运动缺陷的易感性.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 遗传学 是一个
- 发展生物学 发展生物学
背景情况:
- 成人发病的神经退行性疾病,如前性痴呆症 (FTD) 和肌缩性侧面硬化症 (ALS),源于在胚胎发育期间经常表达的遗传突变.
- 这些突变对神经发育的确切影响,以及它们对疾病发病的后续影响仍然在很大程度上是未知的.
研究的目的:
- 研究C9ORF72重复扩张是FTD和ALS的常见遗传原因,它如何影响胚胎神经发育.
- 确定这种扩张影响大脑发育和疾病易感性的特定机制.
主要方法:
- 使用了携带C9ORF72重复扩展的小鼠模型.
- 在胚胎发育过程中评估神经干细胞增殖和大脑区域大小 (皮质,丘脑).
- 研究了从重复扩张中衍生出来的双重复蛋白 (DPR) 的作用.
- 在C9ORF72小鼠中药理学上模仿发育效应,以评估运动功能.
主要成果:
- 发现C9ORF72的重复扩张限制了神经干细胞在子宫中的增殖.
- 在受影响的胚胎中观察到皮层和胸膜尺寸的显著减少.
- DPR,以前未知会影响神经元活力,被确定为影响神经发育的关键因素.
- 这些发育效应的药物诱导加剧了C9ORF72小鼠的运动缺陷.
结论:
- C9ORF72重复扩张直接影响胚胎大脑发育,特别是影响运动功能至关重要的区域.
- 双重复蛋白在调解这些神经发育缺陷方面起着意想不到的作用.
- 早期的神经发育变化有助于C9ORF72相关的FTD和ALS的发病和发病.
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