장우영 (경희대학교)

한빛사논문

조회425

경희대학교

Mol. Psychiatr., Published 17 October 2022 | https://doi.org/10.1038/s41380-022-01822-1 Cntnap2-dependent molecular networks in autism spectrum disorder revealed through an integrative multi-omics analysis

Wooyoung Eric Jang1,12, Ji Hwan Park 2,12, Gaeun Park3, Geul Bang4, Chan Hyun Na5, Jin Young Kim4, Kwang-Youl Kim6, Kwang Pyo Kim1,7, Chan Young Shin 8, Joon-Yong An 9, Yong-Seok Lee3 and Min-Sik Kim 2,10,11,*

1Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Republic of Korea. 2Department of New Biology, DGIST, Daegu 42988, Republic of Korea. 3Department of Physiology, Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. 4Biomedical Omic Research Group, Korea Basic Science Institute, Ochang 28119, Republic of Korea. 5Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 6Department of Clinical Pharmacology, Inha University Hospital, Incheon 22212, Republic of Korea. 7Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea. 8School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul 05029, Republic of Korea. 9Department of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul 02841, Republic of Korea. 10New Biology Research Center, DGIST, Daegu 42988, Republic of Korea. 11Center for Cell Fate Reprogramming and Control, DGIST, Daegu 42988, Republic of Korea. 12These authors contributed equally: Wooyoung Eric Jang, Ji Hwan Park.

*Corresponding author.

Abstract

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.

논문정보

형식Research article
게재일2022년 10월 (BRIC 등록일 2022-10-27)
연구진국내(교신)+국외 연구진
분야 생명과학 > 생화학

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