Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders

The molecular composition of the excitatory synapse is incompletely defined due to its dynamic nature across developmental stages and neuronal populations. To address this gap, we apply proteomic mass spectrometry to characterize the synapse in multiple biological models, including the fetal human brain and human induced pluripotent stem cell (hiPSC)-derived neurons. To prioritize the identified proteins, we develop an orthogonal multi-omic screen of genomic, transcriptomic, interactomic, and structural data. This data-driven framework identifies proteins with key molecular features intrinsic to the synapse, including characteristic patterns of biophysical interactions and cross-tissue expression. The multi-omic analysis captures synaptic proteins across developmental stages and experimental systems, including 493 synaptic candidates supported by proteomics. We further investigate three such proteins that are associated with neurodevelopmental disorders-Cullin 3 (CUL3), DEAD-box helicase 3 X-linked (DDX3X), and Y-box binding protein-1 (YBX1)-by mapping their networks of physically interacting synapse proteins or transcripts. Our study demonstrates the potential of an integrated multi-omic approach to more comprehensively resolve the synaptic architecture.

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Publication Details

Journal
Cell Systems
Published
2025-03-06
DOI
https://doi.org/10.1016/j.cels.2025.101204
Citations
3
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
2.42

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article

Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders

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3 citations
Cell Systems
Ubiquitin and proteasome pathways
2.42
article

Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders

Kate Licon, Lilia M. Iakoucheva, Sarah N. Wright, Guoping Feng, Gentry N. Patrick, Brent Wilkinson, Xinzhu Tan, Nicolas G. Hartel, Richard D. Smith, Hema Kopalle, Nevan J. Krogan, Ilse Flores, Lara E. Dozier, Maya L. Gosztyla, Justin McKetney, Derek Hong, John J. Y. Lee, Marcelo P. Coba, Stephen K. Gilmore-Hall, Dylan Fong, Weijun Qian, Alexi Nott, Sophie Liu, G Yeo, Jason F. Kreisberg, Danielle L. Swaney, Trey Ideker, Jing Chen, Mei Yuan, Michael Chen, Yang Zhou, Nicholas A. Graham, Charlotte A Marquez, Shuhao Xu, D. S. Tsai, Marina A. Gritsenko
article en
3 citations

Abstract

The molecular composition of the excitatory synapse is incompletely defined due to its dynamic nature across developmental stages and neuronal populations. To address this gap, we apply proteomic mass spectrometry to characterize the synapse in multiple biological models, including the fetal human brain and human induced pluripotent stem cell (hiPSC)-derived neurons. To prioritize the identified proteins, we develop an orthogonal multi-omic screen of genomic, transcriptomic, interactomic, and structural data. This data-driven framework identifies proteins with key molecular features intrinsic to the synapse, including characteristic patterns of biophysical interactions and cross-tissue expression. The multi-omic analysis captures synaptic proteins across developmental stages and experimental systems, including 493 synaptic candidates supported by proteomics. We further investigate three such proteins that are associated with neurodevelopmental disorders-Cullin 3 (CUL3), DEAD-box helicase 3 X-linked (DDX3X), and Y-box binding protein-1 (YBX1)-by mapping their networks of physically interacting synapse proteins or transcripts. Our study demonstrates the potential of an integrated multi-omic approach to more comprehensively resolve the synaptic architecture.

Cell SystemsVol. 16(4)
University of Southern California (US), Montreal Neurological Institute and Hospital (CA), Gladstone Institutes (US), Pacific Northwest National Laboratory (US), McGovern Institute for Brain Research (US), University of California San Diego (US), UK Dementia Research Institute (GB)
National Science Foundation, U.S. Department of Energy, Battelle, Cure Alzheimer's Fund, Alzheimer's Society, Maze Therapeutics, UK Dementia Research Institute, National Institutes of Health, Natural Sciences and Engineering Research Council of Canada, Medical Research Council, Pacific Northwest National Laboratory
Zero hunger
Openalex Percentile: Top 13%
Ubiquitin and proteasome pathways
2.42
DOIOpen Access PDFOpenAlex
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