PQBP1依赖的替代RNA拼接是高卡路里饮食引起的认知障碍的基础
bioRxiv : the preprint server for biology
|June 12, 2025
概括
高脂肪饮食 (HFD) 通过抑制与智力障碍和阿尔茨海默病相关的基因PQBP1来破坏大脑功能,影响突触健康.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 高热量,高脂肪饮食 (HFD) 与大脑疾病有关,但分子机制尚不清楚.
- 一种拼接因子PQBP1与智力障碍和阿尔茨海默病有关.
研究的目的:
- 阐明HFD影响大脑功能的分子机制.
- 调查PQBP1及其相关途径在HFD诱导的大脑功能障碍中的作用.
主要方法:
- RNA测序 (RNAseq) 用于分析HFD养小鼠和PQBP1-条件淘汰 (cKO) 小鼠的替代RNA拼接 (AS).
- 网络分析以确定关键分子和途径.
- 在体外实验中使用初级神经元进行实验.
- 在体内使用腺相关病毒 (AAV) 载体进行的救援实验.
- 免疫组织化学 免疫组织化学
主要成果:
- HFD抑制了PPARγ介导的PQBP1.1的转录.
- 在HFD和PQBP1-cKO小鼠中常见的AS变化会影响与突触相关的基因,将CASK,Cacnb1和Cyfip2确定为关键分子.
- 由HFD诱导的CASK,Cacnb1,Cyfip2和Syt1的AS异型损害了前突触囊泡的释放.
- 在HFD小鼠中,AAV介导的PQBP1,CASK,Cacnb1,Cyfip2或Syt1救援突触和/或认知缺陷的传递.
- 病理轴在刺激神经元和抑制神经元中运行.
结论:
- HFD通过PQBP1-前突触轴诱导大脑功能障碍,涉及改变的RNA拼接.
- 这一途径影响突触囊泡释放和认知功能.
- 这些发现揭示了一个新的分子机制,它是HFD诱导的大脑病理的基础.
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