By Adam Bonislawski
A team of scientists from the Wellcome Trust Sanger Institute and Edinburgh University have completed a proteomic analysis of the human postsynaptic density, identifying 1,461 proteins tied to more than 130 brain diseases.
The study, published this week in the online version of Nature Neuroscience, suggests that synaptic proteins may figure more prominently in nervous system disorders than previously thought and could provide new targets for drug development, Seth Grant, a professor at the Sanger Institute and one of the study's authors, told ProteoMonitor.
The PSD is a cytoskeletal feature at the synaptic junction of brain cells that links together a variety of molecules involved in signal transduction. Researchers have characterized the PSD proteome in organisms like mice and fruit flies, Grant said, but less work on it has been done in humans.
"That's what this study is all about," he said. "Rather than just predict by what we have on mice [PSDs] what [proteins] would be in human PSDs, we wanted to actually measure [the human PSD proteome] directly."
Using LC MS/MS on a Thermo Fisher LTQ FT Ultra mass spectrometer, the researchers identified 1,461 proteins in the PSDs of nine adults, 748 of which were identified in all three replicates. An examination of those 1,461 proteins showed they could be tied to 269 different diseases resulting from mutations in 199 PSD genes.
"We didn't think there would be anything like that number of proteins that were disease relevant in the postsynaptic machinery," Grant said. "We all recognize that synapses are important for disease and that modern psychiatric drugs act on synapses, but nobody would have guessed that there would have been as many as 200 different genes responsible for over 130 different [nervous system] diseases."
In all, the researchers were able to tie roughly 14 percent of all PSD genes to diseases, a number that Grant suggested will likely rise as gene association studies identify new mutations tied to nervous system diseases.
"Most of this is only on Mendelian genetic disorders," he said. "And with genome projects identifying new mutations, we expect more mutations in synaptic proteins to be identified."
Among the diseases the study linked to PSD proteins are common neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's; cognitive disorders like mental retardation; and motor disorders like ataxia and dystonia. The research also linked PSD proteins to a variety of rarer neurological ailments, which, Grant noted, could have implications for drug development.
"Many of these diseases are quite rare, and the drug industry by and large isn't interested in rare diseases because there aren't enough patients for there to be a market for them," he said. "But it could well be that you could develop new drugs to the postsynaptic density that could be useful in treating a whole variety of diseases. If it were possible to develop a treatment for one of those diseases you might realize the treatment could be used for other diseases caused by mutations in the postsynaptic density."
Grant acknowledged, however, that just because a protein tied to a disease state is found in the PSD doesn't mean that the disease stems from mutations affecting the PSD proteome. Many of the proteins the study identified are expressed both in the PSD and elsewhere in the brain and body, he noted, making it "difficult to know if it's because of [their] effect on the postsynaptic density that these mutations are producing these diseases."
To address this issue the team performed a gene set enrichment analysis to isolate the phenotypes most relevant for the PSD, identifying 21 neural phenotypes for which PSD was significantly enriched, primarily involving cognition and motor functions.
"[The study] really puts some numbers on the table for the postsynaptic density," Grant said. "For example, when we talk about the enriched phenotypes we can see that there are 40 human genes in the postsynaptic density involved in mental retardation. It's a large-scale molecule mapping project that allows us to see the importance [of the region]."
The researchers also used the proteomic data to generate a protein interaction map of the PSD, which, Grant said, he thought was "the first one that's ever been made."
"I think [the interaction map] is going to be very useful," he said. "It will allow us to [look at] subsets of genes responsible for sets of phenotypes – cognitive phenotypes, motor phenotypes – and ask, 'Where do they fit on these protein interaction maps? Are they connected? What are the enzymes that are also connected? Is it possible to develop drug targets based on them?'"
Grant expects the availability of proteomic data for human PSDs will draw increased interest from drugmakers to the structure. "There really hasn't been much in the way of human synapse proteomic data, and pharma has always been interested in human synapses as opposed to rodent synapses," he said. "So, I think it's time for pharma to have another look."
The proteomic data could also provide a starting point for researchers investigating the genetic basis of brain diseases by suggesting targets for sequencing, Grant said.
"[Researchers] can say, 'Here [is] a set of candidate proteins at the synapse – we should be sequencing the genes [that produce these proteins] in patients with brain diseases and identifying new mutations.'"
He also hopes the work will encourage other groups to build proteomic profiles of PSDs in subjects with various neurological disorders, suggesting that ideally some sort of international initiative might be launched with this aim in mind.
"Clearly what one would like to know is in what way are synapses different in [patients with] those different diseases – in Alzheimer's, in schizophrenia, in epilepsy," he said. "This sort of dataset is a useful template upon which those disease analyses can be built."
All data from the project is available online at Genes to Cognition, an international collaborative program launched by Grant and supported by the Wellcome Trust exploring the biology of synapses.
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