The genetic basis of 130 brain diseases

Dec 19, 2010

In research published today, scientists have studied human brain samples to isolate a set of proteins that accounts for over 130 brain diseases. The paper also shows an intriguing link between diseases and the evolution of the human brain.

Brain diseases are the leading cause of medical disability in the developed world according to the World Health Organisation and the economic costs in the USA exceeds $300 billion.

The is the most complex organ in the body with millions of connected by billions of . Within each synapse is a set of proteins, which, like the components of an engine, bind together to build a molecular machine called the postsynaptic density – also known as the PSD. Although studies of animal synapses have indicated that the PSD could be important in human diseases and behaviour, surprisingly little was known about it in humans.

A team of scientists, led by Professor Seth Grant at the Wellcome Trust Sanger Institute and Edinburgh University, have extracted the PSDs from synapses of patients undergoing brain surgery and discovered their molecular components using a method known as proteomics. This revealed that 1461 proteins, each one encoded by a different gene, are found in human synapses. This has made it possible, for the first time, to systematically identify the diseases that affect human synapses and provides a new way to study the evolution of the brain and behaviour.

"We found that over 130 brain diseases involve the PSD – far more than expected," says Professor Grant. "These diseases include common debilitating diseases such as Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders as well as epilepsies and childhood developmental diseases including forms of autism and learning disability."

"Our findings have shown that the human PSD is at centre stage of a large range of human diseases affecting many millions of people," says Professor Grant.

"Rather than 'rounding up the usual suspects', we now have a comprehensive molecular playlist of 1000 suspects," says Professor Jeffrey L Noebels, Professor of Neurology, Neuroscience and Human Genetics at Baylor College of Medicine. "Every seventh in this line-up is involved in a known clinical disorder, and over half of them are repeat offenders. Mining the postsynaptic proteome now gives researchers a strategic entry point, and the rest of us a front row seat to witness neuroscience unravel the complexity of human brain disorders."

The findings open several new paths toward tackling these diseases.

"Since many different diseases involve the same set of proteins we might be able to develop new treatments that could be used on many diseases", says Professor Grant. To aid in this objective the group has created the first molecular network, a roadmap of the molecular organisation of human synapses, which shows how the many proteins and diseases are interconnected. "We also can see ways to develop new genetic diagnostic tests and ways to help doctors classify the brain diseases".

To accelerate discovery and application of their data, the scientists have released all their data into the public domain on their website – G2Cdb. The team suggests that the data on the proteome of the PSD will be extremely useful for understanding the brain in the same way the genome was useful for understanding DNA.

The scientists were able to use their study of diseases to identify the biological roots of human behaviour. They found that proteins in the PSD are especially important for cognitive behaviours such as learning and memory, emotion and mood, as well as social behaviours and addiction or drug abuse. The findings provide deep insights into how a DNA mutation can impact on fundamental aspects of our behaviour.

The team examined the rate of evolution of the PSD proteins over millions of years of mammalian evolution, expecting the proteins to evolve at the same rate as other proteins. In a fascinating and unexpected twist to the story, the team found that the PSD proteins changed much more slowly than expected, revealing that the PSD has been highly conserved or constrained from changing during evolution.

"The conservation of the structure of these proteins suggests that the behaviours governed by the PSD and the diseases associated with them have not changed much over many millions of years," said Professor Grant. "It also shows that synapses in rodents are much more similar to humans than we expected showing that mice and rats are suitable models for studying human brain disease."

Professor Jonathan R Seckl, Moncrieff-Arnott Professor of Molecular Medicine and Executive Dean, College of Medicine and Veterinary Medicine, The Queen's Medical Research Institute, Edinburgh, says: "This splendid collaborative study is a major step forward which will surely illuminate the causes of many of the major mental health and neurological disorders that are so common in Britain as well as indicating new ways to develop treatments for these most disabling diseases."

This project was conducted as part of the Genes to Cognition Program, which is a research program aimed at understanding the molecular basis of behaviour and brain disease.

Explore further: Why your favourite song takes you down memory lane

More information: Bayes A et al. (2010) Characterisation of the proteome, diseases and evolution of the human postsynaptic density. Nature Neuroscience. Published online before print at doi: 10.1038/nn.2719

Related Stories

Multiple axons and actions with PSD-95

Dec 15, 2008

Nitric oxide gets neurons together. And it seems to do it backward. Work by Nikonenko et al. suggests that a protein called PSD-95 prompts nitric oxide release from postsynaptic dendritic spines, prompting ...

SUMO wrestling in the brain

May 07, 2007

Increasing the amount of SUMO, a small protein in the brain, could be a way of treating diseases such as epilepsy and schizophrenia, reveal scientists at the University of Bristol, UK. Their findings are published online ...

Developmental brain disorders studied

Jul 06, 2006

U.S. scientists say a recent genetic study of developmental brain disorders might lead to a better understanding of a number of congenital diseases.

MIT reports key pathway in synaptic plasticity

May 21, 2007

Scientists are keenly studying how neurons form synapses--the physical and chemical connections between neurons--and the "pruning" of neural circuits during development, not least because synaptic abnormalities may partially ...

Dynamic molecular mechanism to keep brain activity stable

Jul 13, 2009

In the brain, many types of synaptic proteins are spatio-temporally regulated to maintain synaptic activity at a constant level. Here, the Japanese research group led by Professor Masaki Fukata, Drs. Yuko Fukata and Jun Noritake ...

Recommended for you

Why your favourite song takes you down memory lane

8 hours ago

Music triggers different functions of the brain, which helps explain why listening to a song you like might be enjoyable but a favourite song may plunge you into nostalgia, scientists said on Thursday.

Transcranial Magnetic Stimulation of brain boosts memory

9 hours ago

Stimulating a particular region in the brain via non-invasive delivery of electrical current using magnetic pulses, called Transcranial Magnetic Stimulation, improves memory, reports a new Northwestern Medicine ...

User comments : 0