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The schizophrenia-associated variant in SLC39A8 alters protein glycosylation in the mouse brain

Molecular Psychiatry volume 27, pages 1405–1415 (2022)Cite this article

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Abstract

A missense mutation (A391T) in SLC39A8 is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain is unknown. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. Glycosylation of Asn residues in glycoproteins (N-glycosylation) was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible regional variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, nearly one-third of detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia, such as cell adhesion molecules and neurotransmitter receptors that are expressed across all cell types. These findings provide a mechanistic link between a risk allele and potentially reversible biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia and a novel opportunity for therapeutic development.

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Fig. 1: A391T alters brain N-glycans in a region-dependent manner.
Fig. 2: RNAseq analysis identifies minimal gene expression changes in the cortex and cerebellum of A391T mice.
Fig. 3: A391T mouse cortex has altered N-glycosylation of one-third of glycoproteins originating from all cell types.

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Data availability

The data generated during this study are included in this published article and its supplementary information files, and available from the corresponding author on reasonable request. Raw MS glycomics data files are available through GlycoPOST [69] with the dataset identifier GPST000213. The RNAseq data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus [70, 71] and are accessible through GEO Series accession number GSE184516. The MS data were deposited at the ProteomeXchange Consortium [72] via the PRIDE partner repository and are available with the identifier PXD021632.

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Acknowledgements

This work was supported by a foundation grant from the Stanley Center for Psychiatric Research at the Broad Institute of Harvard/MIT (awarded to RGM) and NIH grants P41GM103694 and R24GM137763 (awarded to RDC), and P30DK040561 (awarded to RIS). RGM is supported by T32MH112485 and a Dupont Warren Fellowship. CMW is supported by NIH NCI U01CA242098.

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Authors and Affiliations

  1. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Robert G. Mealer, Sarah E. Williams, Edward M. Scolnick & Jordan W. Smoller

  2. Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Robert G. Mealer & Jordan W. Smoller

  3. National Center for Functional Glycomics, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Robert G. Mealer, Sarah E. Williams, Maxence Noel & Richard D. Cummings

  4. The Stanley Center for Psychiatric Research at Broad Institute of Harvard/MIT, Cambridge, MA, USA

    Robert G. Mealer, Edward M. Scolnick & Jordan W. Smoller

  5. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Bo Yang, Alexandria K. D’Souza & Christina M. Woo

  6. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Toru Nakata, Daniel B. Graham, Elizabeth A. Creasey & Ramnik J. Xavier

  7. Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Toru Nakata, Daniel B. Graham, Elizabeth A. Creasey, Murat Cetinbas, Ruslan I. Sadreyev & Ramnik J. Xavier

  8. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Toru Nakata, Daniel B. Graham, Elizabeth A. Creasey & Ramnik J. Xavier

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  1. Robert G. Mealer
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Contributions

RGM conceptualized the project, performed the bulk of experiments and analyses, and wrote the manuscript. SEW performed glycomics experiments and assisted with statistical analysis. MN performed quantitative glycan analyses and lectin blotting. BY and ADS performed glycoproteomic analysis. TN assisted in tissue harvest, genotyping, and mouse colony maintenance. DBG was involved in mouse generation. EAC was involved in mouse generation, genotyping, and colony maintenance. MC performed analysis of RNAseq data. RIS supervised RNAseq analysis. EMS initiated the project and coordinated collaborations. CMW supervised BY and ADS and oversaw glycoproteomic analysis. JWS co-supervised RGM and SEW, oversaw experimental analyses, and helped conceptualize the project. RJX provided mouse samples for analysis. RDC co-supervised RGM, SEW, and MN, oversaw experimental analyses, and helped conceptualize the project. All authors contributed feedback and edit to the manuscript.

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Correspondence to Robert G. Mealer.

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Competing interests

RJX is a cofounder and equity holder of Celsius Therapeutics and Jnana Therapeutics and consultant to Novartis. These companies did not provide support for this work. JWS is a member of the Scientific Advisory Board of Sensorium Therapeutics and has received honoraria for an internal seminar at Biogen, Inc and Tempus Labs. These companies did not provide support for this work. The remaining authors declare no competing interests.

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Mealer, R.G., Williams, S.E., Noel, M. et al. The schizophrenia-associated variant in SLC39A8 alters protein glycosylation in the mouse brain. Mol Psychiatry 27, 1405–1415 (2022). https://doi.org/10.1038/s41380-022-01490-1

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