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

Nadeem Murtaza; Annie A Cheng; Chad O Brown; Durga Praveen Meka; Shuai Hong; Jarryll A Uy; Joelle El-Hajjar; Neta Pipko; Brianna K Unda; Birgit Schwanke; Sansi Xing; Bhooma Thiruvahindrapuram; Worrawat Engchuan; Brett Trost; Eric Deneault; Froylan Calderon de Anda; Bradley W Doble; James Ellis; Evdokia Anagnostou; Gary D Bader; Stephen W Scherer; Yu Lu; Karun K Singh

doi:10.1016/j.celrep.2022.111678

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

Cell Rep. 2022 Nov 22;41(8):111678. doi: 10.1016/j.celrep.2022.111678.

Authors

Nadeem Murtaza¹, Annie A Cheng², Chad O Brown¹, Durga Praveen Meka³, Shuai Hong³, Jarryll A Uy⁴, Joelle El-Hajjar⁵, Neta Pipko⁵, Brianna K Unda², Birgit Schwanke³, Sansi Xing⁵, Bhooma Thiruvahindrapuram⁶, Worrawat Engchuan⁶, Brett Trost⁶, Eric Deneault⁷, Froylan Calderon de Anda³, Bradley W Doble⁸, James Ellis⁹, Evdokia Anagnostou¹⁰, Gary D Bader¹¹, Stephen W Scherer⁹, Yu Lu⁵, Karun K Singh¹²

Affiliations

¹ Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; Krembil Research Institute, University Health Network, Toronto, ON, Canada.
² Krembil Research Institute, University Health Network, Toronto, ON, Canada.
³ Center for Molecular Neurobiology Hamburg (ZMNH), Research Group Neuronal Development, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
⁴ Krembil Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁵ Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
⁶ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
⁸ Department of Paediatrics, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
⁹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Neurology, The Hospital for Sick Children, Toronto, ON, Canada; Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.
¹¹ Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹² Krembil Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: karun.singh@uhnresearch.ca.

PMID: 36417873
DOI: 10.1016/j.celrep.2022.111678

Abstract

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.

Keywords: BioID; CP: Neuroscience; adaptive behavior score; autism spectrum disorder; genetics; metabolism; mitochondria; neurodevelopment; neurodevelopmental disorders; proteomics; socialization score.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autism Spectrum Disorder* / genetics
Autistic Disorder* / genetics
Humans
Neurons
Protein Interaction Maps / genetics
Proteins
Wnt Signaling Pathway

Substances

Proteins