Postsynaptic Density Genes Linked to Multitude of Brain Disorders

The postsynaptic density (PSD), an enigmatic structure located in some brain cell synapses, was analyzed at the proteomic and genomic levels and found to be the source of proteins involved in more than 130 brain diseases.

The PSD is a physical feature of the cytoskeleton found in some synapses of brain cells. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron. A PSD's molecular scaffolding is usually composed of L-glutamate neurotransmitter receptors. PSDs also contain cell adhesion molecules and a diverse set of other signaling proteins. PSDs vary in size and composition among brain regions, varying in size from about 250 nm to 500 nm in diameter and 25 nm to 50 nm in thickness, depending on the activity state of the synapse.

In the current study, investigators at the Wellcome Trust Sanger Institute (Hinxton, United Kingdom) isolated the postsynaptic density from human neocortex (hPSD) from patients undergoing brain surgery. The material was examined at both the genomic and proteomic levels. Results published in the December 19, 2010, online edition of the journal Nature Neuroscience revealed that the investigators had identified 1,461 distinct proteins. Mutations among the genes coding for these proteins were linked to 133 neurological and psychiatric diseases.

"We found over 130 brain diseases involve the PSD -- far more than expected," said senior author Dr. Seth Grant, a principle investigator at the Wellcome Trust Sanger Institute. "The human PSD is at center stage of a large range of human diseases affecting millions of people. The conservation of the structure of these proteins suggests that the behaviors governed by the PSD and the diseases associated with them have not changed much over many millions of years."

"We can also see ways to develop new genetic diagnostic tests and help doctors classify the brain diseases," said Dr. Grant.

In an effort to boost PSD research, the investigators have created and released into the public domain a "molecular roadmap" for human synapses showing how the 1,461 proteins and the 130 diseases interconnect.

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Wellcome Trust Sanger Institute