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母亲X染色体影响雌性小鼠的认知和大脑衰老

Samira Abdulai-Saiku¹, Shweta Gupta¹, Dan Wang¹

¹Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

|January 22, 2025

概括

一个活跃的母体X染色体 (Xm) 损害了认知能力,并加速了雌性小鼠的大脑衰老. 激活静止的Xm基因改善了认知功能, 这表明老年女性认知衰退的治疗目标.

科学领域:

神经科学
遗传学
老龄化研究

背景情况:

雌性哺乳动物拥有两个X染色体 (Xm,Xp),其中一个在发育过程中失活,导致可变的X染色体马赛克.
由X染色体来源的表观遗传修饰可能会影响健康和疾病,但功能影响仍然不清楚.
了解X染色体马赛克对于解释女性的认知变异至关重要.

研究的目的:

研究X染色体歪曲的功能后果,特别是活跃的母性X染色体 (Xm),对雌性小鼠的大脑功能和衰老的影响.
识别与主动Xm和主动父X染色体 (Xp) 相关的独特神经特征.

主要方法:

对不同程度的X染色体停活的雌性小鼠进行比较分析 (Xm与Xp活跃).
评估整个生命周期的认知功能和海马衰老标志物.
海马神经元的表观遗传分析,包括DNA甲基化和基因印记.
通过CRISPR介导的基因激活来测试特定的印记基因对认知的影响.

主要成果:

一个活跃的Xm染色体在雌性小鼠的一生中损害了认知功能,随着年龄的增长,缺陷变得更严重.
在海马体中加速生物和表观遗传衰老.
在海马神经元的Xm染色体上发现了一些与认知相关的基因.
激活这些印制的Xm基因改善了老年雌性小鼠的认知缺陷.

结论:

母亲的X染色体 (Xm) 可以对认知功能产生负面影响,并加速女性的大脑衰老.
基因印记在Xm染色体上使与认知相关的基因沉默,导致与年龄相关的认知衰退.
针对Xm印制基因为减轻女性认知缺陷和脑衰老提供了潜在的治疗策略.

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