Autism spectrum disorder (ASD) is a major neurodevelopmental disorder in which patients present with core symptoms of social communication impairment, restricted interest, and repetitive behaviors. Although various studies have been performed to identify ASD-related mechanisms, ASD pathology is still poorly understood. CNTNAP2 genetic variants have been found that represent ASD genetic risk factors, and disruption of Cntnap2 expression has been associated with ASD phenotypes in mice. In this study, we performed an integrative multi-omics analysis by combining quantitative proteometabolomic data obtained with Cntnap2 knockout (KO) mice with multi-omics data obtained from ASD patients and forebrain organoids to elucidate Cntnap2-dependent molecular networks in ASD. To this end, a mass spectrometry-based proteometabolomic analysis of the medial prefrontal cortex in Cntnap2 KO mice led to the identification of Cntnap2-associated molecular features, and these features were assessed in combination with multi-omics data obtained on the prefrontal cortex in ASD patients to identify bona fide ASD cellular processes. Furthermore, a reanalysis of single-cell RNA sequencing data obtained from forebrain organoids derived from patients with CNTNAP2-associated ASD revealed that the aforementioned identified ASD processes were mainly linked to excitatory neurons. On the basis of these data, we constructed Cntnap2-associated ASD network models showing mitochondrial dysfunction, axonal impairment, and synaptic activity. Our results may shed light on the Cntnap2-dependent molecular networks in ASD.
Bibliographical noteFunding Information:
We thank members in the laboratory of KPK and M-SK for their assistance, and MK and CR for tissue dissection. This study was supported by the NRF Brain Research Program funded by the Ministry of Science and ICT of Republic of Korea (2017M3C7A1027472 to M-SK) and by the National Research Foundation of Korea (NRF) grants funded by the Korea government (2020R1C1C1003426 to JYA; 2022R1A2C2013377 to M-SK; 2018H1A2A1062533 to WEJ; 2018H1A2A1061381 to GP; 2018R1A5A2025964 to Y-SL; DGIST R&D program [22-CoE-BT-04] to M-SK).
© 2022, The Author(s).
ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Molecular Biology