Exosc2 deficiency leads to developmental disorders by causing a nucleotide pool imbalance in zebrafish
Exosc2 deficiency leads to developmental disorders by causing a nucleotide pool imbalance in zebrafish
复制标题
Exosc2 缺陷会导致斑马鱼核苷酸库失衡，从而导致发育障碍
DOI：
10.1016/j.bbrc.2020.10.044
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发表时间：
2020
影响因子：
3.1
通讯作者：
Hanada Toshikatsu
中科院分区：
文献类型：
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作者：
Yatsuka Hiroyuki;Hada Kazumasa;Shiraishi Hiroshi;Umeda Ryohei;Morisaki Ikuko;Urushibata Hirotaro;Shimizu Nobuyuki;Sebastian Wulan Apridita;Hikida Takatoshi;Ishitani Tohru;Hanada Reiko;Shimada Tatsuo;Kimoto Kenichi;Kubota Toshiaki;Hanada Toshikatsu
Exosc2是外泌体复合物的组成部分之一，参与RNA 3'末端加工和各种RNA的降解。最近，德国家庭中报道了 EXOSC2 突变，导致身材矮小、听力损失、色素性视网膜炎和过早衰老。然而，EXOSC2 的体内功能一直难以捉摸。在此，我们培育了 Exosc2 敲除 (exosc2−/−) 斑马鱼，该斑马鱼在受精后 13 天表现出幼虫致死性，伴有小头畸形、脊髓运动神经元丧失、髓磷脂缺乏和色素性视网膜炎。从机制上讲，Exosc2 缺陷会导致 mRNA 周转受损，从而导致核苷酸库失衡。雷帕霉素通过抑制 mTOR 通路来调节 mRNA 周转，改善了 exosc2−/− 斑马鱼的核苷酸池不平衡，从而延长了存活时间并部分挽救了神经元缺陷。总而言之，我们的研究结果为 Exosc2 缺陷引起的疾病发病机制提供了新的见解，并可能有助于解释神经元疾病的基本分子机制，例如阿尔茨海默病、肌萎缩侧索硬化症和脊髓性肌萎缩症。
Exosc2 is one of the components of the exosome complex involved in RNA 3′ end processing and degradation of various RNAs. Recently,EXOSC2mutation has been reported in German families presenting short stature, hearing loss, retinitis pigmentosa, and premature aging. However, thein vivofunction of EXOSC2 has been elusive. Herein, we generated Exosc2 knockout (exosc2−/−) zebrafish that showed larval lethality 13 days post fertilization, with microcephaly, loss of spinal motor neurons, myelin deficiency, and retinitis pigmentosa. Mechanistically, Exosc2 deficiency caused impaired mRNA turnover, resulting in a nucleotide pool imbalance. Rapamycin, which modulated mRNA turnover by inhibiting the mTOR pathway, improved nucleotide pool imbalance inexosc2−/−zebrafish, resulting in prolonged survival and partial rescue of neuronal defects. Taken together, our findings offer new insights into the disease pathogenesis caused by Exosc2 deficiency, and might help explain fundamental molecular mechanisms in neuronal diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and spinal muscular atrophy.