Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes
Bayés, Àlex (Institut d'Investigació Biomèdica Sant Pau)
Collins, Mark O. (University of Sheffield (Regne Unit))
Galtrey, Clare M. (St George's Hospital (Londres, Regne Unit))
Simonnet, Clémence (University of Edinburgh (Regne Unit))
Roy, Marcia (University of Edinburgh (Regne Unit))
Croning, Mike D.R. (University of Edinburgh (Regne Unit))
Gou Alsina, Gemma (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Van De Lagemaat, Louie N. (University of Edinburgh (Regne Unit))
Milward, David (Linguamatics (Cambridge, Regne Unit))
Whittle, Ian R. (University of Edinburgh (Regne Unit))
Smith, Colin (University of Edinburgh (Regne Unit))
Choudhary, Jyoti S (Wellcome Trust Sanger Institute (Hinxton,Regne Unit))
Grant, S.G.N. (University of Edinburgh (Regne Unit))
Universitat Autònoma de Barcelona

Data:	2014
Resum:	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.
Ajuts:	European Commission 242498
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	MAGUK ; Mass spectrometry ; Post-mortem brain ; Proteomics ; Psychiatric disorder ; Supercomplex ; Synapse
Publicat a:	Molecular Brain, Vol. 7 Núm. 1 (2014) , ISSN 1756-6606

DOI: 10.1186/s13041-014-0088-4
PMID: 25429717

11 p, 1007.3 KB

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