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January 2011



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First Published Thursday, 21 May 2009

Don Powell


Scientists at the Wellcome Trust Sanger Institute have discovered a set of brain proteins responsible for some of the most common and devastating brain diseases. The proteins underlie epilepsy, depression, schizophrenia, bipolar disease, mental retardation and neurodegenerative diseases including Alzheimer’s and Huntington’s diseases.

The reason such a remarkable number of diseases are relevant to this set of proteins is that these proteins are at the heart of how brain cells function,” explains Professor Seth Grant, Director of the Genes to Cognition Programme at the Wellcome Trust Sanger Institute.

Rather than taking traditional methods for studying just one protein at a time, the researchers developed a method that finds whole sets of proteins that bind to each other and form microscopic molecular machines. They were hunting for the ‘engine room’ of nerve cells, which is known to be inside the connections between nerve cells called synapses.

Synapses join the billions of nerve cells together in the brain and they are the location where learning and memory and many other behaviors are controlled.

We developed a new method, which led to this discovery,” says Dr Jyoti Choudhary, leader of the Proteomic Mass Spectrometry team, which collaborated with Professor Grant’s team on the study, “and it should be equally useful in finding the basis of many other diseases in other cells and tissues of the body.

To find this key set of proteins – called MASCs (a scientific acronym for MAGUK Associated Signaling Complexes and pronounced ‘mask’) – the researchers adapted a method that had previously been used in yeast cells.

These approaches have enabled the most specific interrogation of the synapse, in terms of its constituent complexes and have revealed that genes associated with brain diseases such as schizophrenia are highly over represented within this molecular machine,” says Dr Mark Collins, author on the study from the Sanger Institute. “This is a landmark in terms of characterisation of truly endogenous protein complexes or ‘molecular machines’, as this is the first time it has been conducted in a higher organism in this way.

The method involved making a ‘molecular hook’ and attaching it to one protein inside brain cells of mice. They then caught the hook and pulled it out and found it brought along another 100 proteins. The set contained dozens of disease causing proteins.

This points to the new concept that the molecular machines are defective in the diseases and that they present new ways to approach therapy,” says Dr Choudhary.

Not only were there many disease proteins within the molecular machines but also proteins that control the communication between nerve cells and the mechanisms of learning and memory.

This research is an important convergence of basic and clinical science,” says Professor Grant. “Our findings are exciting because they suggest that the molecular machine itself is at the root of many important brain diseases. This was a blue-skies research project seeking the basic mechanisms of learning and memory and it has led us into some of the inner workings of the brain.

This is a key step toward new ways to fight mental illness.

This research was part of the Genes to Cognition Programme, that is an international research consortium based in the UK and directed by Professor Grant. The research program also maintains the G2COnline an education and public understanding of science website.

Fernández E, Collins MO, Uren RT, et al. Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins. Mol Syst Biol. 2009 May;5:269 doi:10.1038/msb.2009.27   [Full text]

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