机构：[1]Furong Laboratory, Center for Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics, Hunan InternationalScientific and Technological Cooperation Base of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha 410078 Hunan, China[2]OujiangLaboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China[3]Townsend Family Laboratories, Department of Psychiatry, TheUniversity of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada[4]Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, School ofMental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China[5]Advanced Innovation Center for Human Brain Protection, The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing100053, China首都医科大学宣武医院
As the most prevalent neurodevelopmental disorders in children, autism spectrum disorders (ASD) are characterized by deficits in language development, social interaction, and repetitive behaviors or inflexible interests. Contactin associated protein like 2 (CNTNAP2), encoding a single transmembrane protein (CNTNAP2) with 1331 amino acid residues, is a widely validated ASD-susceptible gene. Cntnap2-deficient mice also show core autism-relevant behaviors, including the social deficits and repetitive behavior. However, the cellular mechanisms underlying dysfunction CNTNAP2 and ASD remain elusive. In this study, we found a motif within the transmembrane domain of CNTNAP2 was highly homologous to the gamma-secretase cleavage site of amyloid-beta precursor protein (APP), suggesting that CNTNAP2 may undergo proteolytic cleavage. Further biochemical analysis indicated that CNTNAP2 is cleaved by gamma-secretase to produce the CNTNAP2 intracellular domain (CICD). Virally delivery of CICD to the medial prefrontal cortex (mPFC) in Cntnap2-deficient (Cntnap2(-/-)) mice normalized the deficit in the ASD-related behaviors, including social deficit and repetitive behaviors. Furthermore, CICD promoted the nuclear translocation of calcium/calmodulin-dependent serine protein kinase (CASK) to regulate the transcription of genes, such as Prader Willi syndrome gene Necdin. Whereas Necdin deficiency led to reduced social interaction in mice, virally expression of Necdin in the mPFC normalized the deficit in social preference of Cntnap2(-/-) mice. Our results thus reveal a critical function of CICD and highlight a role of the CNTNAP2-CASK-Necdin signaling pathway in ASD.
基金：
National Natural Science Foundation of China (NSFC) [81770780, 31972913]; Key Research and Development Programs from Hunan Province [2021DK2001]; Guangdong Key Project in Development of New Tools for Diagnosis and Treatment of Autism' [2018B030335001]; Strategic Priority Research Program of Central South University [ZLXD2017004]; Independent Exploration and Innovation Project of Central South University [2018zzts393]
第一作者机构：[1]Furong Laboratory, Center for Medical Genetics, Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics, Hunan InternationalScientific and Technological Cooperation Base of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha 410078 Hunan, China
共同第一作者：
通讯作者：
通讯机构：[2]OujiangLaboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China[3]Townsend Family Laboratories, Department of Psychiatry, TheUniversity of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada[4]Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, School ofMental Health and Kangning Hospital, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
推荐引用方式(GB/T 7714)：
Zhang Jing,Cai Fang,Lu Renbin,et al.CNTNAP2 intracellular domain (CICD) generated by gamma-secretase cleavage improves autism-related behaviors[J].SIGNAL TRANSDUCTION AND TARGETED THERAPY.2023,8(1):doi:10.1038/s41392-023-01431-6.
医学