异染色体异常和双链RNA积累是多重毒性的基础
Yong-Jie Zhang1,2, Lin Guo3, Patrick K Gonzales4
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Science (New York, N.Y.)
|February 16, 2019
概括
在C9orf72中重复扩张会导致前性痴呆 (FTD) 和ALS. 一个新的小鼠模型显示, 氨酸蛋白质会破坏大脑细胞,
科学领域:
- 神经科学
- 遗传学
- 分子生物学
背景情况:
- C9orf72基因的六核酸重复扩张是前性痴呆症 (FTD) 和肌性侧面硬化症 (ALS) 的主要原因.
- 这些扩张导致神经退行的精确分子机制在很大程度上是未知的.
研究的目的:
- 通过开发表达疾病相关蛋白质的小鼠模型来研究C9orf72重复扩张的致病机制.
- 阐明多元蛋白质如何导致FTD和ALS的神经功能障碍和神经退行.
主要方法:
- 从扩展的GGGGCC (G4C2) 重复合成的表达多基因蛋白质的转基因小鼠模型的开发.
- 对神经病理特征进行脑组织分析,包括缩,神经元损失,质和蛋白质局部化.
- 研究聚烯对细胞结构的影响,包括异染色素,HP1α,基因组甲基化和核膜.
主要成果:
- 在小鼠大脑中表达的多PR会导致脑缩,神经元损失和结质症.
- 发现多种蛋白质可以结合DNA,局部化为异色素,并破坏HP1α液相组织.
- 观察到基因组甲基化,HP1α表达和核膜结构的异常,与重复元素表达和dsRNA积累相关.
结论:
- 在C9orf72相关的FTD和ALS的发病过程中,通过破坏异色素结构和基因调节,多种蛋白质发挥着关键作用.
- 这些发现为C9orf72相关的神经退行性疾病的分子机制提供了新的见解.
- 开发的小鼠模型为进一步研究FTD和ALS提供了宝贵的工具.
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