Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells  

作　　者：Yeming Yang Guo Huang Xiaoyan Jiang Xiao Li Kuanxiang Sun Yi Shi Zhenglin Yang Xianjun Zhu 

机构地区：[1]The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine,Center for Medical Genetics,Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu,Sichuan 610072,China [2]Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026),Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital,Chengdu,Sichuan 610072,China [3]Key Laboratory of Tibetan Medicine Research,Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research,Northwest Institute of Plateau Biology,Xining,Qinghai 810008,China

出　　处：《Journal of Genetics and Genomics》2022年第9期847-858,共12页遗传学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82121003,81970841,and 81790643);the Department of Science and Technology of Sichuan Province(2021YFS0386,2021YFS0369,20ZYD038,20ZYD037,2020JDZH0026,2021JDZH0022);the CAMS Innovation Fund for Medical Sciences(2019-12M-5-032);Huanhua Distingished Scholar grant;the Department of Chengdu Science and Technology(2021-YF05-01316-SN)。

摘　　要：N^(6)-methyladenosine(m^(6)A)modification,which is achieved by the METTL3/METTL14/WTAP methyltransferase complex,is the most abundant internal mRNA modification.Although recent evidence indicates that m^(6)A can regulate neurodevelopment as well as synaptic function,the roles of m^(6)A modification in the cerebellum and related synaptic connections are not well established.Here,we report that Purkinje cell(PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death.Loss of Wtap also causes the aberrant degradation of multiple PC synapses.WTAP depletion leads to decreased expression levels of METTL3/14 and reduced m^(6)A methylation in PCs.Moreover,the expression of GFAP and NF-L in the degenerating cerebellum is increased,suggesting severe neuronal injuries.In conclusion,this study demonstrates the critical role of WTAP-mediated m^(6)A modification in cerebellar PCs,thus providing unique insights related to neurodegenerative disorders.

关 键 词：N^(6)-methyladenosine Wtap METTL3 METTL14 Purkinje cell ATAXIA CEREBELLUM 

分 类 号：R744.7[医药卫生—神经病学与精神病学]