Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions
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.
Authors
- S. Alexandra Garcia-Moreno (ORCID: https://orcid.org/0000-0003-2137-6114)
- Jieqing Zhao (ORCID: https://orcid.org/0000-0002-0134-7538)
- Matthew Trn
- William C. Wetsel (ORCID: https://orcid.org/0000-0002-3592-7397)
- Joseph D. Buxbaum (ORCID: https://orcid.org/0000-0001-8898-8313)
- Laura Sloofman (ORCID: https://orcid.org/0000-0001-7628-4378)
- Erik J. Soderblom (ORCID: https://orcid.org/0000-0002-6765-1786)
- Yong‐hui Jiang (ORCID: https://orcid.org/0000-0001-6188-8806)
- Dmitry Velmeshev (ORCID: https://orcid.org/0000-0002-6491-7307)
- Daichi Shonai (ORCID: https://orcid.org/0000-0001-5430-6185)
- Géraldine Dawson (ORCID: https://orcid.org/0000-0003-1410-2764)
- Charles A. Gersbach (ORCID: https://orcid.org/0000-0003-1478-4013)
- Scott H. Soderling (ORCID: https://orcid.org/0000-0001-7808-197X)
- Yudong Gao (ORCID: https://orcid.org/0000-0002-2371-4693)
Institutions
- Allen Institute for Brain Science (US)
- Duke University (US)
- Baylor College of Medicine (US)
- Yale University (US)
- Child Health and Development Institute (US)
- Duke Medical Center (US)
- Applied Genetic Technologies (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1038/s41467-024-51037-x
- Citations
- 23
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 12.66
Funders
- National Institutes of Health
- National Institute of Mental Health