Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

Laura Sichlinger; Maximilian  Hausherr; Sara Guerrisi; Lucia Dutan Polit; George Chennell; Roland Nagy; Rugile Matuleviciute; Fatema Nasser; Szidónia Farkas; Rosemary Bamford; Szi Kay Leung; Rodrigo R.R. Duarte; Timothy Powell; Jonathan Mill; Katrin Marcus; Anthony Vernon; Deepak Srivastava

doi:10.1126/sciadv.aea0755

Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

Laura Sichlinger
, Maximilian Hausherr
, Sara Guerrisi
, Lucia Dutan Polit
, George Chennell
, Roland Nagy
, Rugile Matuleviciute
, Fatema Nasser
, Szidónia Farkas
, Rosemary Bamford
, Szi Kay Leung
, Rodrigo R.R. Duarte
, Timothy Powell
, Jonathan Mill
, Katrin Marcus
, Anthony Vernon
, Deepak Srivastava^*

^*Corresponding author for this work

King's College London
University of Exeter Medical School
GSTT Guy's and St Thomas' NHS Foundation Trust
Ruhr-University Bochum

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Abstract

ZNF804A was among the first genes robustly associated with schizophrenia based on findings from large-scale genomic studies. Previous research has implicated ZNF804A in the regulation of gene expression and synaptic function, but the role of this gene in neurodevelopment and in schizophrenia pathogenesis remains unclear. To study its function during neurodevelopment, we generated isogenic human induced pluripotent stem cells with reduced ZNF804A expression, differentiated them into developing cortical glutamatergic neurons, and studied their transcriptomic, synaptic, and protein signatures. Mutant neurons showed modest evidence for changes in gene expression. However, high-content confocal imaging revealed increased excitatory synapse density in mutant neurons. Cell compartment-specific proteomic analysis further revealed that mutant neurons had higher levels of ribosomal and translational proteins within neurites, and high-content imaging confirmed increased local protein synthesis efficiency. Overall, these results demonstrate that in human developing cortical glutamatergic neurons, ZNF804A regulates excitatory synapse formation potential via increased local protein translation.

Original language	English
Article number	eaea0755
Pages (from-to)	eaea0755
Journal	Science Advances
Volume	12
Issue number	21
DOIs	https://doi.org/10.1126/sciadv.aea0755
Publication status	Published - 20 May 2026

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Sichlinger_etal_MainText_R4_mergedAccepted author manuscript, 42 MBLicence: CC BY

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Sichlinger, L., Hausherr, M., Guerrisi, S., Dutan Polit, L., Chennell, G., Nagy, R., Matuleviciute, R., Nasser, F., Farkas, S., Bamford, R., Leung, S. K., Duarte, R. R. R., Powell, T., Mill, J., Marcus, K., Vernon, A., & Srivastava, D. (2026). Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons. Science Advances, 12(21), eaea0755. Article eaea0755. https://doi.org/10.1126/sciadv.aea0755

@article{02ed3d535e344746a2c6b08833f98c07,

title = "Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons",

abstract = "ZNF804A was among the first genes robustly associated with schizophrenia based on findings from large-scale genomic studies. Previous research has implicated ZNF804A in the regulation of gene expression and synaptic function, but the role of this gene in neurodevelopment and in schizophrenia pathogenesis remains unclear. To study its function during neurodevelopment, we generated isogenic human induced pluripotent stem cells with reduced ZNF804A expression, differentiated them into developing cortical glutamatergic neurons, and studied their transcriptomic, synaptic, and protein signatures. Mutant neurons showed modest evidence for changes in gene expression. However, high-content confocal imaging revealed increased excitatory synapse density in mutant neurons. Cell compartment-specific proteomic analysis further revealed that mutant neurons had higher levels of ribosomal and translational proteins within neurites, and high-content imaging confirmed increased local protein synthesis efficiency. Overall, these results demonstrate that in human developing cortical glutamatergic neurons, ZNF804A regulates excitatory synapse formation potential via increased local protein translation.",

author = "Laura Sichlinger and Maximilian Hausherr and Sara Guerrisi and \{Dutan Polit\}, Lucia and George Chennell and Roland Nagy and Rugile Matuleviciute and Fatema Nasser and Szid{\'o}nia Farkas and Rosemary Bamford and Leung, \{Szi Kay\} and Duarte, \{Rodrigo R.R.\} and Timothy Powell and Jonathan Mill and Katrin Marcus and Anthony Vernon and Deepak Srivastava",

note = "Data, Code, and Materials Availability: All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials or from publicly accessible repositories. Proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository under the dataset identifier PXD047788—https://ebi.ac.uk/pride/archive/projects/PXD047788. RNA-seq data are available from the Gene Expression Omnibus (GEO—https://ncbi.nlm.nih.gov/geo/) with accession number GSE254523—https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE254523. The only new materials generated in this study were the mutant ZNF804A cell lines and are described in Materials and Methods. Mutant ZNF804A cell lines are available from the corresponding author upon reasonable request. Requests should be directed to the corresponding author.",

year = "2026",

month = may,

day = "20",

doi = "10.1126/sciadv.aea0755",

language = "English",

volume = "12",

pages = "eaea0755",

journal = "Science Advances",

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Sichlinger, L, Hausherr, M, Guerrisi, S , Dutan Polit, L, Chennell, G, Nagy, R , Matuleviciute, R , Nasser, F , Farkas, S, Bamford, R, Leung, SK, Duarte, RRR, Powell, T , Mill, J, Marcus, K, Vernon, A & Srivastava, D 2026, 'Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons', Science Advances, vol. 12, no. 21, eaea0755, pp. eaea0755. https://doi.org/10.1126/sciadv.aea0755

TY - JOUR

T1 - Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

AU - Sichlinger, Laura

AU - Hausherr, Maximilian

AU - Guerrisi, Sara

AU - Dutan Polit, Lucia

AU - Chennell, George

AU - Nagy, Roland

AU - Matuleviciute, Rugile

AU - Nasser, Fatema

AU - Farkas, Szidónia

AU - Bamford, Rosemary

AU - Leung, Szi Kay

AU - Duarte, Rodrigo R.R.

AU - Powell, Timothy

AU - Mill, Jonathan

AU - Marcus, Katrin

AU - Vernon, Anthony

AU - Srivastava, Deepak

N1 - Data, Code, and Materials Availability: All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials or from publicly accessible repositories. Proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository under the dataset identifier PXD047788—https://ebi.ac.uk/pride/archive/projects/PXD047788. RNA-seq data are available from the Gene Expression Omnibus (GEO—https://ncbi.nlm.nih.gov/geo/) with accession number GSE254523—https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE254523. The only new materials generated in this study were the mutant ZNF804A cell lines and are described in Materials and Methods. Mutant ZNF804A cell lines are available from the corresponding author upon reasonable request. Requests should be directed to the corresponding author.

PY - 2026/5/20

Y1 - 2026/5/20

N2 - ZNF804A was among the first genes robustly associated with schizophrenia based on findings from large-scale genomic studies. Previous research has implicated ZNF804A in the regulation of gene expression and synaptic function, but the role of this gene in neurodevelopment and in schizophrenia pathogenesis remains unclear. To study its function during neurodevelopment, we generated isogenic human induced pluripotent stem cells with reduced ZNF804A expression, differentiated them into developing cortical glutamatergic neurons, and studied their transcriptomic, synaptic, and protein signatures. Mutant neurons showed modest evidence for changes in gene expression. However, high-content confocal imaging revealed increased excitatory synapse density in mutant neurons. Cell compartment-specific proteomic analysis further revealed that mutant neurons had higher levels of ribosomal and translational proteins within neurites, and high-content imaging confirmed increased local protein synthesis efficiency. Overall, these results demonstrate that in human developing cortical glutamatergic neurons, ZNF804A regulates excitatory synapse formation potential via increased local protein translation.

AB - ZNF804A was among the first genes robustly associated with schizophrenia based on findings from large-scale genomic studies. Previous research has implicated ZNF804A in the regulation of gene expression and synaptic function, but the role of this gene in neurodevelopment and in schizophrenia pathogenesis remains unclear. To study its function during neurodevelopment, we generated isogenic human induced pluripotent stem cells with reduced ZNF804A expression, differentiated them into developing cortical glutamatergic neurons, and studied their transcriptomic, synaptic, and protein signatures. Mutant neurons showed modest evidence for changes in gene expression. However, high-content confocal imaging revealed increased excitatory synapse density in mutant neurons. Cell compartment-specific proteomic analysis further revealed that mutant neurons had higher levels of ribosomal and translational proteins within neurites, and high-content imaging confirmed increased local protein synthesis efficiency. Overall, these results demonstrate that in human developing cortical glutamatergic neurons, ZNF804A regulates excitatory synapse formation potential via increased local protein translation.

UR - https://www.scopus.com/pages/publications/105039745826

U2 - 10.1126/sciadv.aea0755

DO - 10.1126/sciadv.aea0755

M3 - Article

SN - 2375-2548

VL - 12

SP - eaea0755

JO - Science Advances

JF - Science Advances

IS - 21

M1 - eaea0755

ER -

Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

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