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

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

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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,ADAM 10/17-dependent a-secretase and presenilin-dependent γ-secretase.We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue 179 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.

Qing Zhang、Mengen Xing、Zhengkai Bao、Lu Xu、Yang Bai、Wanqi Chen、Wenhao Pan、Fang Cai、Qunxian Wang、Shipeng Guo、Jing Zhang、Zhe Wang、Yili Wu、Yun Zhang、Jia-Da Li、Weihong Song

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Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine,Vision and Brain Health),Zhejiang Key Laboratory of Alzheimer's Disease,Zhejiang Provincial Clinical Research Center for Mental Disorders,School of Mental Health and Wenzhou Kangning Hospital,The Second Affiliated Hospital and Yuying Children's Hospital,Institute of Aging,Wenzhou Medical University,Wenzhou,Zhejiang 325035,China

Townsend Family Laboratories,Department of Psychiatry,Brain Research Center,The University of British Columbia,2255 Wesbrook

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

Center for Medical Genetics,Hunan Key Laboratory of Animal Models for Human Diseases,Hunan Key Laboratory of Medical Genetics,Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Diseases,School of Life Sciences,Central South University,Changsha 410078 Hunan,China

The National Clinical Research Center for Geriatric Disease,Xuanwu Hospital,Capital Medical University,Beijing 100053,China

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Key Laboratory of Alzheimer's Disease of Zhejiang Province and Oujiang Laboratory国家自然科学基金UBC Four Year Doctoral Fellowship and DMCBH Innovation Fund Graduate Trainee Award中国博士后科学基金

823016152022M712435

2024

10.1038/s41392-024-01768-6

信号转导与靶向治疗(英文)

信号转导与靶向治疗(英文)

CSTPCD
ISSN：
年,卷(期)：2024.9(4)
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