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In a report published online on Wednesday 18 January in Molecular Systems Biology, researchers at the Wellcome Trust Sanger Institute and the University of Edinburgh show that the proteins that comprise the synapse form a complex and densely connected molecular network. This novel model of a molecular network presents a new way to understand how information is processed in the brain and how mental illnesses arise.
Neural synapses not only transmit but also process impulses ? they translate impulses into information. This gives the synapse a vital role in information processing, behaviour memory and diseases.
Professor Seth Grant and his colleagues have dissected the molecular components of synapses to find what they are made from - their parts' list. They now know that there are over a 1000 proteins that make up synapses and amongst these is a large, vital molecular signalling machine of almost 200 proteins that they call MASC.
"Our work could open up new ways to think about how the brain functions and how it is affected in disease," commented Professor Seth Grant, the project leader at the Wellcome Trust Sanger Institute. "We have shown that this machine ? MASC - is built upon simple principles and that its structure predicts function of its components."
The researchers had already shown that dozens of the proteins making up MASC are essential for learning, for memory and are implicated in human diseases of the nervous system, making it a major focus for research. It is thought that when one of the proteins that make up MASC is lacking or is mutated in a disease, then the overall function of MASC is impaired.
MASC's function is known to be the conversion of the information transmitted in the electrical activity patterns of the brain into biochemical signals. It is like the Enigma Machine of World War II, which was used to convert one code into another. When a molecular cog in MASC is broken, the brain handles information abnormally.
In the new, integrated study, Dr Andrew Pocklington, Dr Douglas Armstrong and Mr Mark Cumiskey working with Professor Grant used protein biochemistry, gene prediction, studies from yeast and Drosophila, disease studies and mathematical modelling to identify the linkage between components of MASC. They could then predict the function of MASC proteins, predict how they might fit together and - key - suggest how they might play a role in disease.
Nearly one-third of MASC proteins are involved in human mental illness, such as schizophrenia, bipolar disorder and mental retardation. Such a large number of proteins implicated in disease and behaviour integrated into a single complex is novel and indicates the importance to human health of this molecular machine.
The team examined how all the proteins that make up MASC fit together. In putting this machine back together they showed that the protein parts made many connections and that the connections could be drawn as a wiring diagram or network.
The network did not consist of equal partners. Like airline networks or electrical grid networks, there are key 'hub' components and the network can be severely disrupted if the hub proteins are disturbed.
Dr Douglas Armstrong, Deputy Director, The Edinburgh Centre for Bioinformatics and a senior author on the paper said: "We were intrigued to see how some of the genes linked to human diseases can be traced back through evolution to yeast and Drosophila.
"The methods used here are very similar to those used to study the information flow across the internet or how groups of people interact socially. For the first time, we have modelled complex activity in nerve cells using these techniques."
The team used mathematical models derived from network analysis to show that the MASC network can answer some unresolved problems in the study of learning and memory.
"We have uncovered a whole new layer of complexity in the brain," continued Professor Grant, "We are beginning to get a first glimpse of simple design principles that underpin this molecular complexity.
"We now have a rational way of understanding why so many genes are involved with learning and memory and why the severity of behavioural impairment varies for different mutations or drugs. With this new understanding, molecular networks can now be superimposed onto the neuronal networks to create new models of the human brain.
"Our goal is to understand how the brain works and thereby to shed light on diseases of the nervous system. One-third of people are affected by disease of the brain and this costs the UK National Health Service more than any other single organ system."
An exciting perspective is that this model will allow new
approaches to the design of drugs to treat mental illnesses. Not only
have they found that many of the MASC proteins are important in
schizophrenia, bipolar disease, mental retardation, but they can make
predictions about the value of new drug targets and genes that might be
mutated in inherited forms of these diseases.
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Study of receptors isolated from brain reveals that NMDA and mGluR are assembled into large complexes of 186 proteins. Neurotransmitter receptor complexes are embedded within the post-synaptic density (PSD), which is visible with electron microscopy and comprises 1124 identified proteins.
Studies show that the NMDA-mGluR receptors are linked via adaptor proteins to signalling enzymes and structural proteins. The adaptor proteins include Membrane-Associated Guanylate Kinase (MAGUK) proteins, which directly bind to NMDA receptors. These 186-protein complexes of NMDA receptors, mGluR receptors, MAGUK proteins and associated molecules are referred to as the NMDA receptor complex/MAGUK-associated signalling complex (NRC/MASC).
Publication details
Pocklington AJ, Cumiskey M, Armstrong JD and Grant SGN
(2006) The proteomes of neurotransmitter receptor complexes form
modular networks with distributed functionality underlying plasticity
and behaviour. Mol. Syst. Biol. 2006 doi:10.1038/msb4100041
Corresponding Author
Professor Seth Grant, Wellcome Trust Sanger Institute
Participating Centres
Websites
Grant Lab, Sanger Institute
Genes2Cognition Programme
Armstrong Lab, University of Edinburgh
School of Informatics, University of Edinburgh
Centre for Neuroscience Research, University of Edinburgh
The Wellcome Trust Sanger Institute was founded in 1992 as the focus for the UK sequencing effort of the human and mouse genomes. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome and one-fifth of the mouse, The Institute is also a major contributor to the mapping and sequencing of the zebrafish genome and genomes of more than 90 disease-causing organisms, including TB and malaria. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, UK. http://www.sanger.ac.uk
The Wellcome Trust is an independent research-funding charity,
established under the will of Sir Henry Wellcome in 1936. It is funded
from a private endowment which is managed with long-term stability and
growth in mind. The Trust's mission is to foster and promote research
with the aim of improving human and animal health.
http://www.wellcome.ac.uk
Henry Wellcome: http://www.wellcome.ac.uk/node7120.html
Contact
Don Powell
Press Officer
Wellcome Trust Sanger Institute
Hinxton, Cambs, CB10 1SA, UK
Tel +44 (0)1223 494 956
Mobile +44 (0)7753 7753 97
Email press.officer@sanger.ac.uk
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