N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer’s disease  

作　　者：Xiong Wang Jiazhao Xie Lu Tan Yanjun Lu Na Shen Jiaoyuan Li Hui Hu Huijun Li Xiaoguang Li Liming Cheng 

机构地区：[1]Department of Laboratory Medicine,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [2]Departments of Pathophysiology,Guangxi Medical University,Nanning 530021,China [3]Department of Pathophysiology,School of Basic Medicine,Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [4]Hepatic Biliary Pancreatic Surgery Department,The Central Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430014,China [5]Clinic Center of Human Gene Research,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China

出　　处：《Translational Neurodegeneration》2023年第1期111-129,共19页转化神经变性病（英文）

基　　金：supported by the National Natural Science Foundation of China(82372337,81500925 to Xiong Wang,81801062 to Xiaoguang Li);Tongji Hospital(HUST)Foundation for Excellent Young Scientist(2020YQ01-11 to Xiong Wang);the Natural Science Foundation of Hubei Province(2022CFB150 to Huijun Li).

摘　　要：Background Synaptic degeneration occurs in the early stage of Alzheimer’s disease(AD)before devastating symptoms,strongly correlated with cognitive decline.Circular RNAs(circRNAs)are abundantly enriched in neural tissues,and aberrant expression of circRNAs precedes AD symptoms,significantly correlated with clinical dementia severity.However,the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice.RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3,N6-adenosine-methyltransferase complex catalytic subunit(METTL3).The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining,co-immunoprecipitation and behavioral testing.Further,a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice,which was mediated by METTL3-dependent N6-methyladenosine(m6A)modification.Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice.MiR-3968/UBE2K was validated as the downstream of circRIMS2.Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B.Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.Conclusions In conclusion,our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968,providing novel therapeutic strategies for AD.

关 键 词：Alzheimer’s disease circRNA Synaptic dysfunction GluN2B UBIQUITINATION 

分 类 号：R749.16[医药卫生—神经病学与精神病学]