Exosc2 is one of the components of the exosome complex involved in RNA 3′ end processing and degradation of various RNAs. Recently, EXOSC2 mutation has been reported in German families presenting short stature, hearing loss, retinitis pigmentosa, and premature aging. However, the in vivo function 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 in exosc2^−/− 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.

Exosc2是参与RNA 3'末端加工和各种RNA降解的外泌体复合物的成分之一。最近，在德国家庭中报告了EXOSC2突变，表现为身材矮小，听力下降，色素性视网膜炎和过早衰老。但是，EXOSC2的体内功能难以捉摸。在这里，我们生成了Exosc2基因敲除（exosc2 ^-/-）斑马鱼，在受精后13天表现出幼虫致死性，伴小头畸形，脊髓运动神经元缺失，髓磷脂缺乏和色素性视网膜炎。从机理上讲，Exosc2缺乏导致mRNA转换受损，导致核苷酸库失衡。雷帕霉素可通过抑制mTOR途径来调节mRNA的转化，从而改善了核苷酸池中的不平衡exosc2 ^-/-斑马鱼，导致神经元缺陷的存活时间延长和部分抢救。综上所述，我们的发现为由Exosc2缺乏症引起的疾病发病机理提供了新的见解，并可能有助于解释神经元疾病（如阿尔茨海默氏病，肌萎缩性侧索硬化症和脊髓性肌萎缩症）的基本分子机制。