UnMASCing Machines in the Brain
More than a century ago anatomists found that the human brain was the most complex organ in the human body. Today, we know it is a network of billions of nerve cells in intimate connections at specialized junctions called synapses.
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 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. We have shown that this machine – MASC – is built upon simple principles and that its structure predicts function of its components.”
Professor Seth Grant The project leader at the Wellcome Trust Sanger Institute
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.
“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.”
Dr Douglas Armstrong Deputy Director, The Edinburgh Centre for Bioinformatics and a senior author on the paper
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. 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.”
Professor Seth Grant Sanger Institute
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.
More information
MASC and synapses
Synapses transmit and process information by detecting patterns of neural activity, resulting in changes in the properties of the neuron. Current models focus on receptors for neural impulses that can be broadly categorised into those that transmit the electrical depolarisation (AMPA receptors) and those that activate signalling and plasticity mechanisms (NMDA and metabotropic receptors (mGluR)).
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).
Participating Centres
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
- School of Informatics, University of Edinburgh, Edinburgh, UK
- Division of Neuroscience, University of Edinburgh, Edinburgh, UK
Publications:
Selected websites
The Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.
The Wellcome Trust and Its Founder
The Wellcome Trust is the most diverse biomedical research charity in the world, spending about £450 million every year both in the UK and internationally to support and promote research that will improve the health of humans and animals. The Trust was established under the will of Sir Henry Wellcome, and is funded from a private endowment, which is managed with long-term stability and growth in mind.
