Friday, December 24, 2010

Secrets of the Synapse

Merry Christmas Eve, y'all! I'm in Texas and therefore blogging in a Texas accent currently. Also, I ate some Tex-Mex, which aside from the vegetable oils and corn and cheese and beans is totally paleo. It is too much to hope that the restaurant we went to used the traditional lard.

But life goes on, the year comes to a close, and earlier this month a lovely "Brief Communication" was published in Nature Neuroscience. Now Nature Neuroscience is some hard core brain journaling. I like to think I know more about the brain than the average soul, but when I read the titles of the articles in Nature Neuroscience, I understand the gist of about half of them.

This paper, "Characterization of the proteome, diseases, and evolution of the human synaptic density" is well worth a squint or two. Here's a full text link. What it comes down to is that the researchers were able to find the actual proteins and their associated genes linked to all sorts of neurological disease via human brain sampling and a rather amazing use of free online databases. It's the wikipedia of neuroscience, without the amateur editing, described in a stunning three pages.

Basically, the researchers took brain neocortex samples from 9 adults and used some advanced chemical sorting techniques to to identify all the proteins in the sample, which was calibrated to be a sample of the nerve synapse (specifically the post-synaptic area). Just as when we call all DNA the "genome," when we identify all the proteins, we have what is called a "proteome."

The 748 proteins found in all three replications of the experiment were recorded into a freely available online database. Then the data were compared to the Online Mendelian Inheritance in Man database, which has information about genetic diseases from linkage studies. Linkage studies are usually done comparing siblings and parents with genetic diseases. If there is enough available data, linkage studies will give you sections of chromosomes, and in some cases, even specific genes associated with the diseases (here's a nice mini-primer on the difference between linkage and association genetic studies - my previous post on migraines reviewed an association genetic study).

In short, our researchers compared the data and found 269 diseases resulting from mutations in 199 genes. 133 of these diseases specifically affect the nervous system (80% central, 20% peripheral). Alzheimer's, Parkinson's, Huntington's diseases and disorders resulting in mental retardation, movement disorders and ataxia, epilepsy, and many rare diseases were all scooped up in this analysis.

Breaking down the data further, the scientists found 21 neural phenotypes (a phenotype is a gene expression - we each have genes for blue eyes or brown eyes or both or neither, but our phenotype is our eye color). A phenotype for mental retardation represented 40 genes, while 20 genes represented spasticity. The large number of genes In these sets are thought to mean that the post-synaptic area of the human brain is exceptionally important in these disorders.

The researchers didn't stop there (we're still on the first page of the paper!) The next step was to compare the human data to the much more specific set of mouse data (more specific because we do all sorts of enlightening but gruesome experiments on mice that we are not able to do on humans) From that they were able to find specific sets of genes related to actual cellular morphology linked to certain, especially important "enriched" phenotypes. The enriched phenotypes, associated with lots of neuronal functioning and disease, include components of known very important signaling mechanisms (the NMDA receptor and associated proteins, for example).

Next the human neural coding sequences were compared with various primates and mice using the dN/dS ratio. This data analysis compares the differences in specific samples (the post-synaptic neuron genes from human and chimpanzees, for example) to the expected (average) rate of genetic change over time. Humans and mice diverged 90 million years ago, yet the post-synaptic neuronal genetic dN/dS ratio was "very significantly" less than the variation between the entire human and mouse genome (we're talking a p value of 10 to the -148). Human neuronal genes were, not surprisingly, also very significantly similar to the primate genes studied compared to the whole human and various primate genomes (with similarly minuscule and thus highly significant p values). Mice and rats diverged 20 million years ago from each other, and their post-synaptic genes are also much more similar than you would expect to each other. All this means that the forces of evolution have conserved these important genes over millions of years, meaning they had better work just so, or your offspring won't survive.

The scientists also compared the conservation of these post-synaptic genes to the genes of other areas of the brain (which are also highly conserved), and found the post-synaptic genes were more conserved than the other brain sets, and also more conserved than other genes for basic cellular components (such as the endoplasmic reticulum, the mitochondria, and the nucleus). Highly interconnected "hub" proteins were also more conserved than other post-synaptic genes, showing that the structure of the synapse seems to mediate the evolutionary conservation of the gene sequences involved.

The human [post-synaptic density sampled for this experiment] has a high degree of molecular complexity, with over 1000 proteins,..combinations of proteins regulate the phenotypes of over 130 brain diseases. It is possible, indeed likely, that the proteins identified represent an overall synaptic parts list, with subsets of synapses containing subsets of these proteins... Our data provide a valuable resource and template for investigating human synapse function and suggest new diagnostic and therapeutic approaches.

I'll say. It might also show us that animal studies involving the synapse might give us fairly accurate information related to humans, especially compared to information obtained from dietary studies or the like. The information from this study is a holiday present to neuroscientists everywhere. And shows us the vast potential of comparing existing databases to new data to create working protein maps of what is actually going on in the synapse or other biologic systems.

Amazing. Nearly miraculous. One way or another, the secrets of our complex brains will eventually be revealed.

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