"<i>Contactin-associated protein-like 2 (CNTNAP2)</i> mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes"

作者全名："Zhang, Qing; Xing, Mengen; Bao, Zhengkai; Xu, Lu; Bai, Yang; Chen, Wanqi; Pan, Wenhao; Cai, Fang; Wang, Qunxian; Guo, Shipeng; Zhang, Jing; Wang, Zhe; Wu, Yili; Zhang, Yun; Li, Jia-Da; Song, Weihong"

作者地址："[Zhang, Qing; Xing, Mengen; Bao, Zhengkai; Xu, Lu; Bai, Yang; Chen, Wanqi; Pan, Wenhao; Cai, Fang; Wu, Yili; Song, Weihong] Wenzhou Med Univ, Oujiang Lab, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Zhejiang Key Lab Alzheimers Dis,Zhejiang Prov Clin, Wenzhou 325035, Zhejiang, Peoples R China; [Zhang, Qing; Xing, Mengen; Bao, Zhengkai; Xu, Lu; Bai, Yang; Chen, Wanqi; Pan, Wenhao; Cai, Fang; Wu, Yili; Song, Weihong] Wenzhou Med Univ, Wenzhou Kangning Hosp, Affiliated Hosp Yuying Childrens Hosp 2, Inst Aging, Wenzhou 325035, Zhejiang, Peoples R China; [Zhang, Qing; Song, Weihong] Univ British Columbia, Dept Psychiat, Townsend Family Labs, Brain Res Ctr, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada; [Wang, Qunxian; Guo, Shipeng; Song, Weihong] Chongqing Med Univ, Chongqing Key Lab Translat Med Res Cognit Dev & Le, Minist Educ, Key Lab Pediat Chongqing,Lab Oncol,Key Lab Child D, Chongqing 400014, Peoples R China; [Zhang, Jing; Li, Jia-Da] Cent South Univ, Ctr Med Genet, Hunan Key Lab Anim Models Human Dis, Sch Life Sci,Hunan Key Lab Med Genet,Hunan Int Sci, Changsha 410078, Hunan, Peoples R China; [Wang, Zhe; Zhang, Yun; Song, Weihong] Capital Med Univ, Xuanwu Hosp, Natl Clin Res Ctr Geriatr Dis, Beijing 100053, Peoples R China"

通信作者："Song, WH (通讯作者)，Wenzhou Med Univ, Oujiang Lab, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Zhejiang Key Lab Alzheimers Dis,Zhejiang Prov Clin, Wenzhou 325035, Zhejiang, Peoples R China.; Song, WH (通讯作者)，Wenzhou Med Univ, Wenzhou Kangning Hosp, Affiliated Hosp Yuying Childrens Hosp 2, Inst Aging, Wenzhou 325035, Zhejiang, Peoples R China.; Song, WH (通讯作者)，Univ British Columbia, Dept Psychiat, Townsend Family Labs, Brain Res Ctr, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.; Song, WH (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Translat Med Res Cognit Dev & Le, Minist Educ, Key Lab Pediat Chongqing,Lab Oncol,Key Lab Child D, Chongqing 400014, Peoples R China.; Li, JD (通讯作者)，Cent South Univ, Ctr Med Genet, Hunan Key Lab Anim Models Human Dis, Sch Life Sci,Hunan Key Lab Med Genet,Hunan Int Sci, Changsha 410078, Hunan, Peoples R China.; Zhang, Y; Song, WH (通讯作者)，Capital Med Univ, Xuanwu Hosp, Natl Clin Res Ctr Geriatr Dis, Beijing 100053, Peoples R China."

来源：SIGNAL TRANSDUCTION AND TARGETED THERAPY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001178696900002

JCR分区：Q1

影响因子：40.8

年份：2024

卷号：9

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein plays a role in its function. However, key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown, and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive. In this report we showed that CNTNAP2 undergoes sequential cleavages by furin, ADAM10/17-dependent alpha-secretase and presenilin-dependent gamma-secretase. We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96, and the main alpha-cleavage product C79 by ADAM10 is required for the subsequent gamma-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the alpha-cleavage to generate C79, and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2-I1254T knock-in mice. Finally, exogenous expression of C79 improves autism-like phenotypes in the Cntnap2(-I1254T) knock-in and Cntnap2(-/- )knockout mice. This data demonstrates that the alpha-secretase is essential for CNTNAP2 processing and its function. Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis, and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment."

基金机构：Key Laboratory of Alzheimer's Disease of Zhejiang Province; National Natural Science Foundation of China [82301615]; DMCBH Innovation Fund Graduate Trainee Award; China Postdoctoral Science Foundation [2022M712435]

基金资助正文：The work was supported by the funding from the Key Laboratory of Alzheimer's Disease of Zhejiang Province and Oujiang Laboratory (W.S.) and National Natural Science Foundation of China: 82301615 (M.X.); Q.Z. was the recipient of UBC Four Year Doctoral Fellowship and DMCBH Innovation Fund Graduate Trainee Award; M.X. is the funding recipient from the China Postdoctoral Science Foundation (grant no. 2022M712435). We thank Dr. Laurence Goutebroze for providing us with CNTNAP2 pathogenic mutation plasmids.