G2C::Proteomics

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

Àlex Bayés*, Louie N van de Lagemaat*, Mark O Collins, Mike DR Croning, Ian R Whittle,
Jyoti S Choudhary and Seth GN Grant
                                                                                                                                       * These authors contributed equally to this work

Synapses play a central role in behaviour and understanding mutations and phenotypes in synapse genes may shed light on evolution of human behaviour and its diseases. Although the molecular composition of human synapses is poorly understood, studies in animal models show postsynaptic proteins are organised into macromolecular complexes collectively known as the postsynaptic density (hPSD). Here we isolate 1461 hPSD proteins from human neocortex and find unexpectedly strong sequence conservation in the hPSD between present-day humans, other primates and rodent lineages spanning ~90 my. The most constrained proteins were hubs organising protein interactions in complexes. Human mutations in hPSD genes result in 133 neurological and psychiatric diseases. Phenotype analyses in humans and mice show a key role for the hPSD relative to other brain proteins in cognitive and motor functions. Subsets of hPSD proteins underlying specific disease phenotypes were identified providing potential therapeutic targets for multiple diseases. These data show postsynaptic complexes were constrained by natural selection during the last 90my and have a major role in brain disease.

HUMAN hPSD SAMPLE LOCATIONS HUMAN hPSD SAMPLE LOCATIONS (Sample Details)

Exact location of nine cortical samples obtained by biopsy and used for postsynaptic density isolation.

Data resources

Supplementary Table 1.Information about biological samples.
Supplementary Table 2a.hPSD protein identifications.
Supplementary Table 2b.hPSD proteomic peptide data.
Supplementary Table 3.Summary of OMIM diseases.
Supplementary Table 4.OMIM diseases identified among total hPSD genes.
Supplementary Table 5a.Summary of Human neural phenotype gene set enrichment analysis.
Supplementary Table 5b.Full human neural phenotype gene set enrichment analysis.
Supplementary Table 6.Brain datasets used in phenotype enrichment analysis (Excel file)
Supplementary Table 7a.Summary of mammalian neural phenotype gene set enrichment analysis.
Supplementary Table 7b.Full mammalian neural phenotype gene set enrichment analysis.
Supplementary Table 8.Comparison of dN/dS between Genome and hPSD.
Supplementary Table 9.Mouse and human datasets dN/dS analysis.
Supplementary Table 10.dN/dS Values for genes expressed in human neurons classified by cellular component.
Supplementary Table 11.dN/dS Values for hub, non-hub and TAP-PSD-95 proteins.
Supplementary Table 12.Mouse to human dN/dS values in hPSD and other organelle proteomes.

FAQs

1. What is the postsynaptic density (hPSD)?
2. What was the experimental design?
3. What is proteomic mass spectrometry?
4. What is dN/dS?
5. What is Online Mendelian Inheritance in Man (OMIM) Database?
6. How are mammalian phenotypes identified?
7. How are human phenotypes identified?