title: Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes.
abstract: BACKGROUND
  Synapses are fundamental components of brain circuits and are disrupted in over 100 neurological and psychiatric diseases. The synapse proteome is physically organized into multiprotein complexes and polygenic mutations converge on postsynaptic complexes in schizophrenia, autism and intellectual disability. Directly characterising human synapses and their multiprotein complexes from post-mortem tissue is essential to understanding disease mechanisms. However, multiprotein complexes have not been directly isolated from human synapses and the feasibility of their isolation from post-mortem tissue is unknown.
  
  
  RESULTS
  Here we establish a screening assay and criteria to identify post-mortem brain samples containing well-preserved synapse proteomes, revealing that neocortex samples are best preserved. We also develop a rapid method for the isolation of synapse proteomes from human brain, allowing large numbers of post-mortem samples to be processed in a short time frame. We perform the first purification and proteomic mass spectrometry analysis of MAGUK Associated Signalling Complexes (MASC) from neurosurgical and post-mortem tissue and find genetic evidence for their involvement in over seventy human brain diseases.
  
  
  CONCLUSIONS
  We have demonstrated that synaptic proteome integrity can be rapidly assessed from human post-mortem brain samples prior to its analysis with sophisticated proteomic methods. We have also shown that proteomics of synapse multiprotein complexes from well preserved post-mortem tissue is possible, obtaining structures highly similar to those isolated from biopsy tissue. Finally we have shown that MASC from human synapses are involved with over seventy brain disorders. These findings should have wide application in understanding the synaptic basis of psychiatric and other mental disorders.
authors.forename: Àlex
authors.initials: À
authors.lastname: Bayés
authors.forename: Mark O
authors.initials: MO
authors.lastname: Collins
authors.forename: Clare M
authors.initials: CM
authors.lastname: Galtrey
authors.forename: Clémence
authors.initials: C
authors.lastname: Simonnet
authors.forename: Marcia
authors.initials: M
authors.lastname: Roy
authors.forename: Mike D R
authors.initials: MD
authors.lastname: Croning
authors.forename: Gemma
authors.initials: G
authors.lastname: Gou
authors.forename: Louie N
authors.initials: LN
authors.lastname: van de Lagemaat
authors.forename: David
authors.initials: D
authors.lastname: Milward
authors.forename: Ian R
authors.initials: IR
authors.lastname: Whittle
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.forename: Jyoti S
authors.initials: JS
authors.lastname: Choudhary
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
mesh_terms: D002540:Cerebral Cortex / Q000378:metabolism; D002846:Chromatography, Affinity; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011180:Postmortem Changes; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D014015:Tissue Banks
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020543:Proteome; C033652:postsynaptic density proteins