小柯机器人

美国哈佛医学院Jun R. Huh和Brian T. Kalish团队合作在研究中取得进展。他们的研究发现小鼠中的母体免疫激活会破坏胎儿脑中的蛋白稳态。这一研究成果于2020年12月23日发表在国际顶尖学术期刊《自然-神经科学》杂志上。

他们利用单细胞RNA测序分析响应母体免疫激活（MIA）的小鼠胎脑中转录变化，并鉴定了与mRNA翻译、核糖体生物发生和应激信号传导有关的细胞途径中的干扰。他们发现，MIA以白介素17a依赖性的方式激活雄性而不是雌性MIA后代的综合应激反应（ISR），从而降低了整体mRNA的翻译并改变了新生蛋白质组的合成。 此外，ISR激活的阻滞可防止MIA雄性后代的行为异常以及皮层神经活动的增加。他们的数据表明，ISR的性别特异性激活会导致产妇炎症相关的神经发育障碍。

据悉，孕期的母亲感染和炎症与后代的神经发育障碍有关，但对这种流行病学现象背后的分子机制了解甚少。

附：英文原文

Title: Maternal immune activation in mice disrupts proteostasis in the fetal brain

Author: Brian T. Kalish, Eunha Kim, Benjamin Finander, Erin E. Duffy, Hyunju Kim, Casey K. Gilman, Yeong Shin Yim, Lilin Tong, Randal J. Kaufman, Eric C. Griffith, Gloria B. Choi, Michael E. Greenberg, Jun R. Huh

Issue&Volume: 2020-12-23

Abstract: Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders. This paper shows that maternal immune activation in mice induces changes in the mRNA translation machinery in the fetal brain and activates the integrated stress response in male fetuses, which mediates neurobehavioral abnormalities.

DOI: 10.1038/s41593-020-00762-9

Source: https://www.nature.com/articles/s41593-020-00762-9

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex