斑马鱼
生物
色素性视网膜炎
小头畸形
肌萎缩侧索硬化
神经退行性变
损失函数
外小体复合体
突变
LRRK2
遗传学
细胞生物学
神经科学
疾病
医学
核糖核酸
表型
内科学
基因
核糖核酸酶P
作者
Hiroyuki Yatsuka,Koji Hada,Hiroshi Shiraishi,Ryohei Umeda,Ikuko Morisaki,Hirotaro Urushibata,Nobuyuki Shimizu,Wulan Apridita Sebastian,Takatoshi Hikida,Tohru Ishitani,Reiko Hanada,Tatsuo Shimada,Katsuhiko Kimoto,Toshiaki Kubota,Toshikatsu Hanada
标识
DOI:10.1016/j.bbrc.2020.10.044
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI