Proteins in PSD linked to brain diseases

EDINBURGH, Scotland—A team of scientists, led by Prof. SethGrant at the Wellcome Trust Sanger Institute and Edinburgh University, haveextracted the proteins from the postsynaptic density (PSD) of patientsundergoing brain surgery and discovered their molecular components viaproteomics. The work revealed that 1,461 proteins, each one encoded by adifferent gene, are found in human synapses, making it possible for the firsttime to systematically identify the diseases that affect human synapses and providinga new way to study the evolution of the brain and behavior. The research linkedthe proteins to more than 130 brain diseases.

"Using the library of Mendelian disorders, we foundapproximately 200 proteins associated with more than 130 brain diseasesaffecting many millions of people—far more than expected," says Grant. "Thesediseases include common debilitating diseases such as Alzheimer's disease,Parkinson's disease and other neurodegenerative disorders, as well asepilepsies and childhood developmental diseases, including forms of autism andlearning disabilities. Since many different diseases involve the same set ofproteins, we might be able to develop new treatments that could be used on manydiseases."

Grant points out that if this turns out to be the case, drugcompanies would find the situation more attractive, since each disease alonemight be found in a relatively small cohort of patients. To aid in theobjective of linking specific proteins and diseases, the group has created thefirst molecular network, a roadmap of the molecular organization of humansynapses, which shows how the many proteins and diseases are interconnected.

"We also can see ways to develop new genetic diagnostictests and ways to help doctors classify the brain diseases," Grant adds.

"Rather than rounding up the usual suspects, we now have acomprehensive molecular playlist of 1,000 suspects," says Prof. Jeffrey L.Noebels, a neurology professor in Baylor College of Medicine's Neuroscience andHuman Genetics department. "Every seventh protein in this lineup is involved ina known clinical disorder, and over half of them are repeat offenders. Miningthe postsynaptic proteome now gives researchers a strategic entry point, andthe rest of us a front-row seat to witness neuroscience unravel the complexityof human brain disorders."

Brain diseases are the leading cause of medical disabilityin the developed world, according to the World Health Organization, and theeconomic costs in the United States exceed $300 billion annually. To acceleratediscovery and application of their data, the scientists have released all theirdata into the public domain on their website, G2Cdb. The researchers were ableto use their study of diseases to identify the biological roots of human behavior.They found that proteins in the PSD are especially important for cognitivebehaviors such as learning and memory, emotion and mood, as well as socialbehaviors and addiction or drug abuse.

The team examined the rate of evolution of the PSD proteins,expecting the proteins to evolve at the same rate as other proteins. In anunexpected twist to the story, the team found that the PSD proteins changedmuch more slowly than expected, revealing that the PSD has been highlyconserved or constrained from changing during evolution.

"The conservation of the structure of these proteinssuggests that the behaviors governed by the PSD and the diseases associatedwith them have not changed much over many millions of years," Grant notes. "Italso shows that synapses in rodents are much more similar to humans than weexpected showing that mice and rats are suitable models for studying humanbrain disease."

This study was made possible by a collaboration betweenthree specialist teams, including neurosurgeon Prof. Ian Whittle at EdinburghUniversity, the protein mass spectrometry facility led by Drs. Jyoti Choudharyand Mark Collins at the Sanger Institute, and neuroscientists and computerbiologists Drs. Alex Bayés, Louie Van de Lagemaat and Mike Croning. This projectwas conducted as part of the Genes to Cognition Program, which is a researchprogram aimed at understanding the molecular basis of behavior and braindisease.