Abstract
One of the main drivers of autism spectrum disorder (ASD) are risk alleles within hundreds of genes, which may interact within shared biological processes through as-yet unclear mechanisms. Here we develop a high-throughput genome-editing-mediated approach to target 14 high-confidence ASD genes within the mouse brain for proximity-based proteomics of endogenous interactomes. The resulting interactomes are enriched for human genes dysregulated in the brain of ASD patients and reveal unexpected, but highly significant, interactions with other lower confidence ASD-risk gene products, positing new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the disorder. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two ASD models, demonstrating new functional interactions that modulate mechanisms of their dysregulation. Together, our results reveal native protein-interaction networks in ASD, providing new inroads for understanding its cellular neurobiology.
Competing Interest Statement
SS and YG have a patent related to the HiUGE technology. The intellectual property was licensed to CasTag Biosciences. SS is a founder of CasTag Biosciences; Duke University as an institution holds equity in CasTag Biosciences. CAG is an inventor on patents and patent applications related to CRISPR-based gene activation, is a co-founder of Tune Therapeutics, Locus Biosciences, and Element Genomics, and is an advisor to Sarepta Therapeutics. GD Dr. Dawson is on the Scientific Advisory Boards of Akili Interactive, Inc, and Tris Pharma, is a consultant to Apple, Gerson Lehrman Group, and Guidepoint Global, Inc. GD has developed autism-related technology, data, and/or products that have been licensed to Apple, Inc. and Cryocell, Inc. and Dawson and Duke University have benefited financially. JDB is a consultant for Bridgebio.
