Scholars@Duke publication: Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions.

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

Publication , Journal Article

Gao, Y; Shonai, D; Trn, M; Zhao, J; Soderblom, EJ; Garcia-Moreno, SA; Gersbach, CA; Wetsel, WC; Dawson, G; Velmeshev, D; Jiang, Y-H ...

Published in: Nat Commun

August 9, 2024

Published version (DOI) Link to item

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.

Duke Scholars

Author Geraldine Dawson Psychiatry, Child & Family Mental Health & Community Psychia ...

Author Scott Haydn Soderling Cell Biology

Author Charles Gersbach Biomedical Engineering

Author Dmitry Velmeshev Neurobiology

Author Erik James Soderblom Cell Biology

Author William Christopher Wetsel Psychiatry & Behavioral Sciences, Behavioral Medicine & Neur ...

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Published In

Nat Commun

DOI

10.1038/s41467-024-51037-x

EISSN

2041-1723

Publication Date

August 9, 2024

Volume

Issue

Start / End Page

6801

Location

England

Related Subject Headings

Proteomics
Proteome
Phenotype
Mice, Inbred C57BL
Mice
Male
Humans
Genetic Predisposition to Disease
Gene Editing
Female

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Chicago

ICMJE

MLA

NLM

Gao, Y., Shonai, D., Trn, M., Zhao, J., Soderblom, E. J., Garcia-Moreno, S. A., … Soderling, S. H. (2024). Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions. Nat Commun, 15(1), 6801. https://doi.org/10.1038/s41467-024-51037-x

Gao, Yudong, Daichi Shonai, Matthew Trn, Jieqing Zhao, Erik J. Soderblom, S Alexandra Garcia-Moreno, Charles A. Gersbach, et al. “Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions.” Nat Commun 15, no. 1 (August 9, 2024): 6801. https://doi.org/10.1038/s41467-024-51037-x.

Gao Y, Shonai D, Trn M, Zhao J, Soderblom EJ, Garcia-Moreno SA, et al. Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions. Nat Commun. 2024 Aug 9;15(1):6801.

Gao, Yudong, et al. “Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions.” Nat Commun, vol. 15, no. 1, Aug. 2024, p. 6801. Pubmed, doi:10.1038/s41467-024-51037-x.

Gao Y, Shonai D, Trn M, Zhao J, Soderblom EJ, Garcia-Moreno SA, Gersbach CA, Wetsel WC, Dawson G, Velmeshev D, Jiang Y-H, Sloofman LG, Buxbaum JD, Soderling SH. Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions. Nat Commun. 2024 Aug 9;15(1):6801.