Defining the Human Synapse Proteome

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Clinical Brain Sciences

Abstract

Nerve cells are connected through their branches (axons and dendrites) by specialised structures known as synapses. Each nerve cell has hundreds to thousands of synapses that connect the neurons in the brain into networks of immense complexity. The synapse is considered to be the fundamental functional unit of the nervous system and performs the role of transmitting the electrical information or activity in one nerve cell to the next, typically by releasing neurotransmitters across the synaptic cleft. Neurotransmitters and their receptors are defective in many brain diseases and are also the target of the majority of drugs used to treat brain diseases. Moreover, these synaptic neurotransmitters are affected by drugs of abuse. Understanding the human synapse is clearly important for human disease.

Despite the central importance of synapses, surprisingly little is known about human synapses. The main objective of this project is to identify the proteins that comprise human synapses and study their differences in parts of the brain and between species. We will focus on key sets of proteins at synapses that bind together and form ?multiprotein complexes?. These are molecular machines that detect patterns of electrical activity in the synapse and control learning and memory and many other behaviours. The proteins that comprise these machines are involved in many human brain diseases and are of great potential as therapeutic targets for future medicines.

The information from this research will be disseminated freely and be important for driving future research programs. The explanation of the experiments and their implications will also be made available to the public through an educational website (http://www.g2conline.org/).

Technical Summary

Synapses are the key component of the nervous system linking nerve cells into circuits. Not only important for transmitting information between neurons, they initiate plasticity underlying learning and memory, are the site of action of most therapeutic and recreational drugs and the locus of numerous disease processes. It is therefore of highest importance to understand the synapse not only in model systems but also in humans.

Our laboratory has pioneered the development of synapse proteomics characterising the first neurotransmitter receptor complex, synapse phosphoproteome and systems biology analysis of the mouse synapse. The synapse proteome is organised into multiprotein complexes that in turn have a network architecture of protein-protein interactions. The best characterised synaptic complexes are the presynaptic neurotransmitter vesicle complexes and the postsynaptic NMDA receptor/MASC complexes, which are embedded in the postsynaptic density. The postsynaptic proteome comprises ~1100 proteins and the NMDA receptor complexes ~185 proteins. Current estimates of the entire synapse proteome complexity are in the range of ~2000 proteins.

Surprisingly little is known about the composition of human brain synapses. We plan to isolate and characterise human brain synapses, the neurotransmitter receptor complexes and postsynaptic density from normal brain. An accumulating body of evidence indicates that the postsynaptic complexes contain many disease genes involved with common and rare conditions.

The high degree of molecular complexity found in the synapse proteome requires specialised informatic tools and approaches. We will exploit systems biology approaches, previously used in mice, to integrate large sets of molecular data thereby generating molecular maps of the human synapse - which will be useful in interpreting disease, genetic, pharmacological and anatomical data. We aim to provide core datasets on the human synapse proteome that will underpin future programs with an impact on human health.

This program will interface with the Genes to Cognition (G2C) program - a UK based international research consortium focussed on molecular function of synapses and bridging human clinical and basic science. G2C has database resources and an educational program that will be available for this project.
 
Description Synaptic Systems: dissecting brain function in health and disease
Amount € 885,400 (EUR)
Funding ID 242167 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 07/2010 
End 12/2014
 
Title Synaptic disease models 
Description Several contributions: 1. Database of synapse proteome has enabled a key publication in Molecular Psychiatry. 2. Analysis has provided new way to classify human brain diseases and symptoms. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2010 
Provided To Others? Yes  
Impact Two manuscripts have been generated from this: 1. Kirov et al, Molecular Psychiatry 2011. This study shows the human postsynaptic density defined in our MRC study is involved in over 130 brain diseases and over 200 gene mutations. 2. Hawrylics et al (Submitted to Nature). This paper combines our proteomic research with transcriptome analysis of the human brain. 
 
Description Human Genetics of Schizophrenia and its impact on the synapse 
Organisation Broad Institute
Country United States of America 
Sector Charity/Non Profit 
PI Contribution Sharing data and design of human genetics study of shizophrenia
Collaborator Contribution Collaboration on a publication.
Impact Paper submitted to Nature showing that the human postsynaptic density is a locus of mutations in schizophrenia.
Start Year 2010
 
Description Human Genetics of the postsynaptic density 
Organisation Cardiff University
Department Psychiatry
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We identified the proteins in the human postsynaptic density and my collaborators identified the mutations in these genes.
Collaborator Contribution We have analysed mutations in schizophrenia patients and identified how they impact on the human synapse. This led to a paper now out for review in Nature.
Impact A paper submitted to Nature, which is not out for review. We beleive this paper reveals that the human neocortex PSD is a key locus of schizophrenia.
Start Year 2010
 
Description The synaptome in bipolar disease 
Organisation Johns Hopkins University
Department School of Medicine Johns Hopkins
Country United States of America 
Sector Academic/University 
PI Contribution We provide knowledge and bioinformatic analysis of synaptic proteins for our partners to analyse mutations in humans.
Collaborator Contribution Understanding of new methods of studying bipolar disease
Impact A successful award of funding from the NIH This is multidisciplinary project: human genetics, human neuroproteomics, bioinformatics
Start Year 2009
 
Description G2Conline 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact online video

explaining gene to cognition research to public
Year(s) Of Engagement Activity 2009
URL http://www.g2conline.org/
 
Description Kenneth B Myer Lecture 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public/ scientific audience talk and outreach event

Stimulated discussion
Year(s) Of Engagement Activity
URL http://www.florey.edu.au/news-events/events-seminars/2014-10-15/kenneth-b-myer-lecture-2014
 
Description Podcast 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact media event

unknown
Year(s) Of Engagement Activity 2013
URL http://brainsciencepodcast.com
 
Description Public Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 200 members of the public at the Newcastle Centre for Life. 100 members of the public at INsPace in Edinburgh.

It was suggested to make the presentation into a television show!
Year(s) Of Engagement Activity 2009,2010
 
Description Public lecture, The Salon Project, Public Meeting, Glasgow, UK; "Madness, Genius and the origin of the brain" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact to complete
Year(s) Of Engagement Activity 2013
 
Description Synapses and Neurodegeneration, Plenary Speaker,Roslin Institute, Edinburgh, UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact to complete
Year(s) Of Engagement Activity 2013