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Characterization of the proteome, diseases and evolution of the human postsynaptic density

Abstract

We isolated the postsynaptic density from human neocortex (hPSD) and identified 1,461 proteins. hPSD mutations cause 133 neurological and psychiatric diseases and were enriched in cognitive, affective and motor phenotypes underpinned by sets of genes. Strong protein sequence conservation in mammalian lineages, particularly in hub proteins, indicates conserved function and organization in primate and rodent models. The hPSD is an important structure for nervous system disease and behavior.

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Figure 1: hPSD diseases and enriched phenotypes.
Figure 2: hPSD sequence conservation.

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Acknowledgements

We thank C.P. Ponting, P.J. Brophy, R.A.W. Frank, N.H. Komiyama, M.V. Kopanitsa, T.J. Ryan and members of the Genes to Cognition Programme for critical comments on the manuscript and for discussions. We thank the tissue donors, without whom this study would have been impossible. A.B. is supported by EMBO and the European Commission. L.N.v.L., M.O.C., M.D.R.C., J.S.C. and S.G.N.G. are supported by the Wellcome Trust. I.R.W. is supported by Scottish Higher Education Funding Council and by grants from the Medical Research Council, the US National Institutes of Health and the Melville Trust.

Author information

Authors and Affiliations

Authors

Contributions

I.R.W. provided brain samples. A.B., M.O.C. and J.S.C. performed proteomic analysis. A.B. performed OMIM, ICD-10 and evolutionary analyses. L.N.v.L. performed network and enrichment analyses. M.D.R.C. integrated data into G2Cdb. L.N.v.L., M.D.R.C., M.O.C., A.B. and S.G.N.G. wrote the manuscript.

Corresponding author

Correspondence to Seth G N Grant.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Methods (PDF 740 kb)

Supplementary Table 1

Information about Biological Samples. (XLS 28 kb)

Supplementary Table 2

Protein Identifications and Proteomic Data. (XLS 445 kb)

Supplementary Table 3

Summary of OMIM Diseases. (XLS 19 kb)

Supplementary Table 4

OMIM Diseases Identified Among Total hPSD Genes. (XLS 141 kb)

Supplementary Table 5

Human Neural Phenotype gene set enrichment analysis. (XLS 93 kb)

Supplementary Table 6

Brain datasets used in phenotype enrichment analysis. (XLS 327 kb)

Supplementary Table 7

Mammalian Neural Phenotype gene set enrichment Analysis. (XLS 187 kb)

Supplementary Table 8

Comparison of dN/dS between Genome and hPSD. (XLS 10375 kb)

Supplementary Table 9

Mouse and Human Brain Datasets dN/dS Analysis. (XLS 740 kb)

Supplementary Table 10

dN/dS Values for genes expressed in human neurons classified by cellular component. (XLS 847 kb)

Supplementary Table 11

Analysis of dN/dS on Hub, non-Hub and TAP-PSD-95 proteins. (XLS 135 kb)

Supplementary Table 12

Mouse to Human dN/dS Values in hPSD and Other Organelle Proteomes. (XLS 3289 kb)

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Bayés, À., van de Lagemaat, L., Collins, M. et al. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat Neurosci 14, 19–21 (2011). https://doi.org/10.1038/nn.2719

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  • DOI: https://doi.org/10.1038/nn.2719

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