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

Yuan Mei¹, Maya L Gosztyla², Xinzhu Tan³, Lara E Dozier⁴, Brent Wilkinson⁵, Justin McKetney⁶, John Lee⁷, Michael Chen⁷, Dorothy Tsai⁷, Hema Kopalle⁸, Marina A Gritsenko⁹, Nicolas Hartel¹⁰, Nicholas A Graham¹⁰, Ilse Flores¹⁰, Stephen K Gilmore-Hall⁴, Shuhao Xu², Charlotte A Marquez⁷, Sophie N Liu⁷, Dylan Fong⁷, Jing Chen⁷, Kate Licon⁷, Derek Hong¹¹, Sarah N Wright⁷, Jason F Kreisberg¹², Alexi Nott¹³, Richard D Smith⁹, Wei-Jun Qian⁹, Danielle L Swaney⁶, Lilia M Iakoucheva¹¹, Nevan J Krogan⁶, Gentry N Patrick⁴, Yang Zhou³, Guoping Feng¹⁴, Marcelo P Coba¹⁵, Gene W Yeo¹⁶, Trey Ideker¹⁷

Affiliations

¹ Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA.
² Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA; Center for RNA Technologies and Therapeutics, University of California, San Diego, La Jolla, CA, USA.
³ Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 1A1, Canada.
⁴ Department of Neurobiology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA.
⁶ Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, Quantitative Biosciences Institute, San Francisco, CA 94158, USA; University of California, San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, CA 94143, USA.
⁷ Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁸ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA.
⁹ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
¹⁰ Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
¹¹ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
¹² Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA.
¹³ Department of Brain Sciences, Imperial College London, White City Campus, London W12 7RH, UK; UK Dementia Research Institute, Imperial College London, White City Campus, London W12 0BZ, UK.
¹⁴ McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁵ Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: coba@usc.edu.
¹⁶ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA; Center for RNA Technologies and Therapeutics, University of California, San Diego, La Jolla, CA, USA. Electronic address: geneyeo@ucsd.edu.
¹⁷ Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: tideker@ucsd.edu.

PMID: 40054464
PMCID: PMC12283108 (available on 2026-03-06)
DOI: 10.1016/j.cels.2025.101204

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

Yuan Mei et al. Cell Syst. 2025.

. 2025 Apr 16;16(4):101204.

doi: 10.1016/j.cels.2025.101204. Epub 2025 Mar 6.

Authors

Affiliations

¹ Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA.
² Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA; Center for RNA Technologies and Therapeutics, University of California, San Diego, La Jolla, CA, USA.
³ Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 1A1, Canada.
⁴ Department of Neurobiology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA.
⁶ Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, Quantitative Biosciences Institute, San Francisco, CA 94158, USA; University of California, San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, CA 94143, USA.
⁷ Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁸ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA.
⁹ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
¹⁰ Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.
¹¹ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
¹² Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA.
¹³ Department of Brain Sciences, Imperial College London, White City Campus, London W12 7RH, UK; UK Dementia Research Institute, Imperial College London, White City Campus, London W12 0BZ, UK.
¹⁴ McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁵ Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: coba@usc.edu.
¹⁶ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92023, USA; Sanford Stem Cell Institute Innovation Center, University of California, San Diego, La Jolla, CA 92037, USA; Center for RNA Technologies and Therapeutics, University of California, San Diego, La Jolla, CA, USA. Electronic address: geneyeo@ucsd.edu.
¹⁷ Division of Genomics and Precision Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: tideker@ucsd.edu.

PMID: 40054464
PMCID: PMC12283108 (available on 2026-03-06)
DOI: 10.1016/j.cels.2025.101204

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.

Keywords: CUL3; DDX3X; YBX1; machine learning; multi-omics; proteomics; synapse.

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Conflict of interest statement

Declaration of interests T.I. is a co-founder of Data4Cure, Inc., is on the scientific advisory board, and has an equity interest. T.I. is on the scientific advisory board of Ideaya Biosciences, Inc. and has an equity interest. T.I. is on the advisory board of the Cell Systems journal. G.W.Y. is a co-founder, member of the board of directors, on the SAB, equity holder, and paid consultant for Eclipse BioInnovations. The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict-of-interest policies. The Krogan Laboratory has received research support from the Journal of Virol. Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. N.J.K. has financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York; Maze Therapeutics; Interline Therapeutics; Rezo Therapeutics; GEn1E Lifesciences, Inc.; and Twist Bioscience Corp. He is on the board of directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and Interline Therapeutics. D.L.S. has financially compensated consulting agreements with Maze Therapeutics and Rezo Therapeutics.

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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