Cargando…
Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes
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 inte...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271336/ https://www.ncbi.nlm.nih.gov/pubmed/25429717 http://dx.doi.org/10.1186/s13041-014-0088-4 |
_version_ | 1782349584997023744 |
---|---|
author | Bayés, Àlex Collins, Mark O Galtrey, Clare M Simonnet, Clémence Roy, Marcia Croning, Mike DR Gou, Gemma van de Lagemaat, Louie N Milward, David Whittle, Ian R Smith, Colin Choudhary, Jyoti S Grant, Seth GN |
author_facet | Bayés, Àlex Collins, Mark O Galtrey, Clare M Simonnet, Clémence Roy, Marcia Croning, Mike DR Gou, Gemma van de Lagemaat, Louie N Milward, David Whittle, Ian R Smith, Colin Choudhary, Jyoti S Grant, Seth GN |
author_sort | Bayés, Àlex |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-014-0088-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4271336 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42713362014-12-20 Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes Bayés, Àlex Collins, Mark O Galtrey, Clare M Simonnet, Clémence Roy, Marcia Croning, Mike DR Gou, Gemma van de Lagemaat, Louie N Milward, David Whittle, Ian R Smith, Colin Choudhary, Jyoti S Grant, Seth GN Mol Brain Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-014-0088-4) contains supplementary material, which is available to authorized users. BioMed Central 2014-11-28 /pmc/articles/PMC4271336/ /pubmed/25429717 http://dx.doi.org/10.1186/s13041-014-0088-4 Text en © Bayés et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Bayés, Àlex Collins, Mark O Galtrey, Clare M Simonnet, Clémence Roy, Marcia Croning, Mike DR Gou, Gemma van de Lagemaat, Louie N Milward, David Whittle, Ian R Smith, Colin Choudhary, Jyoti S Grant, Seth GN Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes |
title | Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes |
title_full | Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes |
title_fullStr | Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes |
title_full_unstemmed | Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes |
title_short | Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes |
title_sort | human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271336/ https://www.ncbi.nlm.nih.gov/pubmed/25429717 http://dx.doi.org/10.1186/s13041-014-0088-4 |
work_keys_str_mv | AT bayesalex humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT collinsmarko humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT galtreyclarem humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT simonnetclemence humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT roymarcia humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT croningmikedr humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT gougemma humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT vandelagemaatlouien humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT milwarddavid humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT whittleianr humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT smithcolin humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT choudharyjyotis humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes AT grantsethgn humanpostmortemsynapseproteomeintegrityscreeningforproteomicstudiesofpostsynapticcomplexes |