通过上游开放的读取框架中断,有针对性的BDNF上调
Ning Feng1, Thomas Goedert1, Nenad Svrzikapa2
1Institute of Developmental and Regenerative Medicine, University of Oxford, IMS-Tetsuya Nakamura Building, Old Road Campus, Roosevelt Dr, Headington, Oxford OX3 7TY, UK; Department of Paediatrics, University of Oxford, Roosevelt Dr, Headington, Oxford OX3 7TY, UK.
Molecular therapy : the journal of the American Society of Gene Therapy
|December 12, 2025
概括
在脑衍生神经营养因子 (BDNF) 转录中的上游开放阅读框架 (uORF) 调节蛋白质输出. 通过基编辑破坏单个uORF启动编码子,增加了BDNF蛋白水平,提供了一个潜在的治疗策略.
科学领域:
- 分子生物学分子生物学
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
背景情况:
- 传递 RNA 的 5' 未翻译区域 (UTR) 含有控制翻译的调控元素.
- 在5' UTR内的上游开放读取 (uORF) 是已知的基因表达的调节者.
- 大脑衍生神经营养因子 (BDNF) 对神经元的生存和功能至关重要,其表达受到严格监管.
研究的目的:
- 调查uORFs在调节BDNF转化中的作用.
- 探索通过uORF操纵调节BDNF蛋白水平的方法.
主要方法:
- 生物信息分析用于预测BDNF 5' UTRs中的uORF.
- 使用reporter构造的uORF函数的实验验证.
- 基因编辑技术 (腺基编辑) 用于破坏特定的uORF.
主要成果:
- 在大多数BDNF转录异型中发现了uORF,有几种实验证实抑制翻译.
- 在非表达的BDNF变体中删除5' UTR外因子导致了记者上调,这取决于uORF和RNA结构.
- 在一个常见的BDNF变体中,基编辑介导的uORF启动密码子的破坏增加了内源BDNF蛋白表达的约1.8倍.
结论:
- uORFs对BDNF的转录后调节有显著的贡献.
- 针对uORFs,特别是通过基编辑,为增强BDNF蛋白表达提供了一个可行的策略.
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