与阿尔茨海默病风险相关的PLCG2表达和拼接的遗传学
Andrew K Turner1, Kennedy Dotson1, Qi Qiao1
1University of Kentucky.
Research square
|June 30, 2025
概括
通过改变PLCG2表达和拼接,PLCG2中的遗传变异会影响阿尔茨海默病 (AD) 风险. 这些发现可能会导致针对PLCG2功能的新的AD治疗方法.
科学领域:
- 神经遗传学 神经遗传学
- 分子生物学分子生物学
- 基因组学就是基因组学.
背景情况:
- 脂酶C玛2 (PLCG2) 与阿尔茨海默病 (AD) 风险有关.
- 遗传变异,包括罕见的误解多态 (rs72824905) 和常见的变异 (rs12445675) 接近长非编码RNA,与AD相关.
- 了解遗传学如何影响PLCG2的表达和拼接对于AD的发病和治疗策略至关重要.
研究的目的:
- 研究阿尔茨海默病 (AD) 相关遗传因素对PLCG2基因表达和拼接模式的影响.
- 阐明特定的PLCG2遗传变异对蛋白质功能和细胞反应的功能后果.
主要方法:
- 使用PCR和qPCR在人类大脑和血液样本中的量化PLCG2异型表达.
- 在BV-2微质细胞中利用小基因测试来评估基因变异rs1071644.4的功能.
- 研究了无意中介衰变 (NMD) 对D65-PLCG2异型和 (Ca+2) 响应在转染的HEK293细胞中的影响.
主要成果:
- 鉴定了新的PLCG2异型:LNC-PLCG2 (与长非编码RNA融合) 和D65-PLCG2 (缺少28号外65bp).
- 与 rs12445675 基因型相关联的 LNC-PLCG2 与 PLCG2 的比例以及 D65-PLCG2 与 rs1071644-T 的比例.
- 已证明rs1071644作为一种功能性SNP,通过促进D65-PLCG2,一种非功能性异型,增加AD风险.
结论:
- 两个阿尔茨海默病 (AD) 遗传风险因素rs12445675和rs1071644通过不同的机制调节AD风险.
- rs12445675影响了LNC-PLCG2与正规PLCG2.2的比率.
- rs1071644 影响 PLCG2 异构体28 拼接,导致非功能 D65-PLCG2 异构体和AD 风险增加.
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