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

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收录情况： ◇ SCIE ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越：领军期刊

作者：
Qing Zhang[1,2] * ; Mengen Xing[1] * ; Zhengkai Bao[1] * ; Lu Xu [1] ; Yang Bai[1] ; Wanqi Chen[1] ; Wenhao Pan[1] ; Fang Cai[1] ; Qunxian Wang[3] ; Shipeng Guo[3] ; Jing Zhang[4] ; Zhe Wang [5] ; Yili Wu[1] ; Yun Zhang[5] ; Jia-Da Li[4] ; Weihong Song [1,2,3,5] ;
机构： [1]Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Zhejiang Key Laboratory of Alzheimer’s Disease, Zhejiang Provincial Clinical ResearchCenter for Mental Disorders, School of Mental Health and Wenzhou Kangning Hospital, The Second Affiliated Hospital and Yuying Children’s Hospital, Institute of Aging, WenzhouMedical University, Wenzhou, Zhejiang 325035, China [2]Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada [3]Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders,Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China [4]Center for MedicalGenetics, Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics, Hunan International Scientific and Technological CooperationBase of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha 410078 Hunan, China [5]The National Clinical Research Center forGeriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
出处：
DOI： 10.1038/s41392-024-01768-6
ISSN：

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 α-secretase and presenilin-dependent γ-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 α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the α-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 α-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.© 2024. The Author(s).

基金：
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.
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出版当年[2023]版：
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
JCR分区：
出版当年[2022]版：
Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CELL BIOLOGY
最新[2023]版：
Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CELL BIOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2022版] 出版当年五年平均 出版前一年[2021版] 出版后一年[2023版]

第一作者：
第一作者机构： [1]Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Zhejiang Key Laboratory of Alzheimer’s Disease, Zhejiang Provincial Clinical ResearchCenter for Mental Disorders, School of Mental Health and Wenzhou Kangning Hospital, The Second Affiliated Hospital and Yuying Children’s Hospital, Institute of Aging, WenzhouMedical University, Wenzhou, Zhejiang 325035, China [2]Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
共同第一作者：
通讯作者：
通讯机构： [1]Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Zhejiang Key Laboratory of Alzheimer’s Disease, Zhejiang Provincial Clinical ResearchCenter for Mental Disorders, School of Mental Health and Wenzhou Kangning Hospital, The Second Affiliated Hospital and Yuying Children’s Hospital, Institute of Aging, WenzhouMedical University, Wenzhou, Zhejiang 325035, China [2]Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada [3]Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders,Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China [5]The National Clinical Research Center forGeriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
推荐引用方式(GB/T 7714)：
Qing Zhang,Mengen Xing,Zhengkai Bao,et al.Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes[J].Signal Transduction And Targeted Therapy.2024,9(1):51.doi:10.1038/s41392-024-01768-6.
APA：
Qing Zhang,Mengen Xing,Zhengkai Bao,Lu Xu,Yang Bai...&Weihong Song.(2024).Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes.Signal Transduction And Targeted Therapy,9,(1)
MLA：
Qing Zhang,et al."Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes".Signal Transduction And Targeted Therapy 9..1(2024):51

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