Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions

Yudong Gao, Daichi Shonai, Matthew Trn, Jieqing Zhao, Erik J. Soderblom, S. Alexandra Garcia-Moreno, Charles A. Gersbach, William C. Wetsel, Geraldine Dawson, Dmitry Velmeshev, Yong-hui Jiang, Laura G. Sloofman, Joseph D. Buxbaum and Scott H. Soderling ()
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Yudong Gao: Duke University School of Medicine
Daichi Shonai: Duke University School of Medicine
Matthew Trn: Duke University School of Medicine
Jieqing Zhao: Duke University
Erik J. Soderblom: Duke University School of Medicine
S. Alexandra Garcia-Moreno: Duke University
Charles A. Gersbach: Duke University School of Medicine
William C. Wetsel: Duke University School of Medicine
Geraldine Dawson: Duke University School of Medicine
Dmitry Velmeshev: Duke University School of Medicine
Yong-hui Jiang: Yale University School of Medicine
Laura G. Sloofman: Icahn School of Medicine at Mount Sinai
Joseph D. Buxbaum: Icahn School of Medicine at Mount Sinai
Scott H. Soderling: Duke University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.

Date: 2024
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DOI: 10.1038/s41467-024-51037-x

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