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

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.

• Authors: 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
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 9 Issue 1 Pg. 51 (Mar 01 2024) ISSN: 2059-3635 [Electronic] England
• PMID: 38424048 (Publication Type: Journal Article)
• Copyright: © 2024. The Author(s).

Chemical References

• Amyloid Precursor Protein Secretases
• Contactins
• CNTNAP2 protein, mouse
• Membrane Proteins
• Nerve Tissue Proteins

Topics

• Animals
• Mice
• Autistic Disorder
• Amyloid Precursor Protein Secretases (genetics)
• Autism Spectrum Disorder (genetics)
• Mutation (genetics)
• Mice, Knockout
• Contactins (genetics)
• Phenotype
• Membrane Proteins (genetics)
• Nerve Tissue Proteins (genetics)