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CNTNAP2 intracellular domain (CICD) generated by γ-secretase cleavage improves autism-related behaviors
Jing Zhang1, Fang Cai2,3, Renbin Lu1
1Furong Laboratory, 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.
Insights
Researchers discovered a new signaling pathway involving CNTNAP2, CASK, and Necdin that plays a crucial role in autism spectrum disorders (ASD). This pathway
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Autism spectrum disorders (ASD) are prevalent neurodevelopmental conditions characterized by social interaction deficits and repetitive behaviors.
- Contactin associated protein like 2 (CNTNAP2) is a validated gene associated with ASD susceptibility.
- The precise cellular mechanisms linking CNTNAP2 dysfunction to ASD remain unclear.
Purpose of the Study:
- To elucidate the cellular mechanisms underlying CNTNAP2 dysfunction in ASD.
- To investigate the potential proteolytic cleavage of CNTNAP2 and its functional consequences.
- To identify novel therapeutic targets for ASD by exploring the CNTNAP2-related signaling pathway.
Main Methods:
- Bioinformatic analysis to identify potential cleavage sites in CNTNAP2.
- Biochemical assays to confirm CNTNAP2 cleavage by γ-secretase.
- Viral delivery of the CNTNAP2 intracellular domain (CICD) and Necdin in a mouse model of ASD (Cntnap2-/- mice).
- Behavioral assessments to evaluate social interaction and repetitive behaviors in mice.
Main Results:
- CNTNAP2 undergoes γ-secretase cleavage, producing the CNTNAP2 intracellular domain (CICD).
- Viral delivery of CICD to the medial prefrontal cortex (mPFC) in Cntnap2-/- mice rescued ASD-related behavioral deficits.
- CICD promotes CASK nuclear translocation, regulating Necdin transcription.
- Necdin expression in the mPFC of Cntnap2-/- mice normalized social interaction deficits.
Conclusions:
- The CNTNAP2-CASK-Necdin signaling pathway is critical for regulating social behaviors relevant to ASD.
- CICD represents a key functional product of CNTNAP2 cleavage with therapeutic potential for ASD.
- Targeting this pathway offers a promising avenue for developing novel ASD interventions.
Abstract:
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 γ-secretase cleavage site of amyloid-β precursor protein (APP), suggesting that CNTNAP2 may undergo proteolytic cleavage. Further biochemical analysis indicated that CNTNAP2 is cleaved by γ-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.
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