Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes
In: Signal Transduction and Targeted Therapy, Jg. 9 (2024), Heft 1, S. 1-12
Online
academicJournal
Zugriff:
Abstract 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.
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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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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Signal Transduction and Targeted Therapy, Jg. 9 (2024), Heft 1, S. 1-12 |
Veröffentlichung: | Nature Publishing Group, 2024 |
Medientyp: | academicJournal |
ISSN: | 2059-3635 (print) |
DOI: | 10.1038/s41392-024-01768-6 |
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