Defining the Human Synapse Proteome
Lead Research Organisation:
Wellcome Sanger Institute
Department Name: Research Directorate
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/).
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.
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.
