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

Murtaza, N.; Cheng, A. A.; Brown, C. O.; Meka, D. P.; Hong, S.; Uy, J. A.; El-Hajjar, J.; Pipko, N.; Unda, B. K.; Schwanke, B.; Xing, S.; Thiruvahindrapuram, B.; Worrawat, E.; Trost, B.; Deneault, E.; Calderon de Anda, F.; Doble, B. W.; Ellis, J.; Anagnostou, E.; Bader, G. D.; Scherer, S. W.; Lu, Y.; Singh, K. K.

doi:10.1101/2022.01.17.476220

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bioRxiv · 10.1101/2022.01.17.476220

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

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Abstract

Manuscript summaryThere 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 (BioID) 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 reveal 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 post-mortem ASD patients. Clustering of risk genes based on PPI networks identifies gene groups corresponding to clinical behavior score severity. Our data reveal that cell type-specific PPI networks can identify individual and convergent ASD signaling networks, provide a method to assess patient variants, and reveal biological insight into disease mechanisms and sub-cohorts of ASD.

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Murtaza, N., Cheng, A. A., Brown, C. O., Meka, D. P., Hong, S., Uy, J. A., El-Hajjar, J., Pipko, N., Unda, B. K., Schwanke, B., Xing, S., Thiruvahindrapuram, B., Worrawat, E., Trost, B., Deneault, E., Calderon de Anda, F., Doble, B. W., Ellis, J., Anagnostou, E., Bader, G. D., Scherer, S. W., Lu, Y., Singh, K. K.. 2022-01-19. Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies. https://doi.org/10.1101/2022.01.17.476220

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