Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease-relevant pathologies

There are hundreds of risk genes associated with autism spectrum disorder (ASD), but signaling networks at the protein level remain unexplored. We use neuron-specific proximity-labeling proteomics (BioID2) to identify protein-protein interaction (PPI) networks for 41 ASD risk genes. Neuron-specific...

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Published inCell reports (Cambridge) Vol. 41; no. 8; p. 111678
Main Authors Murtaza, Nadeem, Cheng, Annie A, Brown, Chad O, Meka, Durga Praveen, Hong, Shuai, Uy, Jarryll A, El-Hajjar, Joelle, Pipko, Neta, Unda, Brianna K, Schwanke, Birgit, Xing, Sansi, Thiruvahindrapuram, Bhooma, Engchuan, Worrawat, Trost, Brett, Deneault, Eric, Calderon de Anda, Froylan, Doble, Bradley W, Ellis, James, Anagnostou, Evdokia, Bader, Gary D, Scherer, Stephen W, Lu, Yu, Singh, Karun K
Format Journal Article
LanguageEnglish
Published United States 22.11.2022
Subjects
Autism Spectrum Disorder - genetics
Autistic Disorder - genetics
Humans
Neurons
Protein Interaction Maps - genetics
Proteins
Wnt Signaling Pathway
BioID
socialization score
genetics
neurodevelopment
proteomics
CP: Neuroscience
mitochondria
adaptive behavior score
metabolism
autism spectrum disorder
neurodevelopmental disorders
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Summary:There are hundreds of risk genes associated with autism spectrum disorder (ASD), but signaling networks at the protein level remain unexplored. We use neuron-specific proximity-labeling proteomics (BioID2) to identify protein-protein interaction (PPI) networks for 41 ASD risk genes. Neuron-specific PPI networks, including synaptic transmission proteins, are disrupted by de novo missense variants. The PPI network map reveals convergent pathways, including mitochondrial/metabolic processes, Wnt signaling, and MAPK signaling. CRISPR knockout displays an association between mitochondrial activity and ASD risk genes. The PPI network shows an enrichment of 112 additional ASD risk genes and differentially expressed genes from postmortem ASD patients. Clustering of risk genes based on PPI networks identifies gene groups corresponding to clinical behavior score severity. Our data report that cell type-specific PPI networks can identify individual and convergent ASD signaling networks, provide a method to assess patient variants, and highlight biological insight into disease mechanisms and sub-cohorts of ASD.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.111678