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Shedding New Light on Brain Evolution, Wellcome Trust Studies Role of Proteins

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Who: Seth Grant
 
Position: Principal Investigator, Wellcome Trust Sanger Institute, 2003 to present; honorary professor, Cambridge University, experimental psychology, 2007 to present
 
Background: Cold Spring Harbor Laboratory, visiting scientist and then research scientist 1985 to 1994; University of Edinburgh, professor of molecular neuroscience, 2000 to current, director of the Centre for Neuroscience, 1997 to 2002
 
Conventional wisdom has had it that more nerves and bigger craniums translated to greater brain power. But in an article in the June 8 online version of Nature Neuroscience, researchers in the United Kingdom and Japan debunk that theory, saying that brain power has much more complex origins.
 
Using proteomic and genomic technologies, they studied about 600 proteins found in mammalian synapses and found that about half of them are also found in invertebrate synapses and that one-quarter are also found in single-cell organisms that don’t even have brains.
 
Their findings have led them to hypothesize that mammalian synapses originated from a proto-synapse found in single-cell animals, and that during the course of evolution this proto-synapse added more synapses, which in turn propelled the evolution of the brain.
 
This week ProteoMonitor spoke with Seth Grant, the corresponding author on the article. Below is an edited version of the conversation.
 

 
Describe for me the proteomics part of your research.
 
The background to this is proteomic work that we have done on mammalian synapses over the last 10 years. We have produced maps of the post-synaptic side of the mammalian synapse in particular. And we have focused largely on macromolecular complexes found at the synapse, and we’ve published a number of papers on that.
 
The biological standpoint is we are very interested in the fact that synapses are so molecularly complex, and how they became complex through the evolutionary and developmental processes, and finally what does that complexity confer upon the nervous system, recognizing that the human brain has something on the order of a million billion synapses and each one of those has about 1,000 proteins.
 
So why has the brain become such an extraordinarily complex entity? And not just why, but how did it get there?
 
What we did was to use our mouse synapse proteome data as a starting point to do a comparative genomic and a comparative proteomic study of different species. What we discovered was that the evolutionary origins of the brain are in a set of synapse molecules that are found in animals that don’t have a nervous system, such as yeast.
 
About 25 percent of post-synaptic proteins are found in yeast, and in those nice simple animals, they control the behavior of those animals and their response to their environments, which is rather a beautiful analogy with what they’re doing in the synapse in the human brain.
 
Does that mean these proteins in the yeast have functions similar to what they do in human synapses?
 
Indeed they do. They’re co-opted into very basic forms of behaviors found in yeast, and in the human brain and in the mammalian brain, they’re co-opted into related kinds of behaviors [that] have become … somewhat more sophisticated and subtle, but fundamentally the same kind of processes.
 
Then by the comparative analysis, the proteomic and the genomic, we found that not all neurons in all species are the same. There had been a simple view around, which is largely based on supposition that neurons are more or less the same in all species: invertebrates and vertebrates have more or less the same type of synapses and neurons.  
 
But we found that the molecular complexity of the post-synaptic proteome of mammals is from the molecular standpoint about twice as complex, particularly in the context of the synapse-specialized proteins, things like receptors and other key signaling proteins. In a nutshell … about a quarter of all the mammalian synapse proteins are [found in] simple animals that have no nervous systems, and that set of proteins represents the ancient or arche- or proto-synapse in its most elementary form.
 
With the evolution of multicellular animals, that ancient, proto-synaptic set of proteins was elaborated upon by the addition of neurotransmitter receptors and other adhesion types of molecules, things that are fairly typical of metazoans, and that set of proteins was then recruited and found its way into synapses of those simple nervous systems. The next step was then the evolution of different vertebrate species, and then there was another major transition where that set of proteins effectively doubled again to produce the large complex sets that are available and exploited by the nervous systems of vertebrate species.
 
I like to sometimes think of it as a simple way, which is a bit like a pyro rocket … it started off with a blast with several hundred proteins and 150 proteins in yeast and then it doubled again. The first booster was into the invertebrates and the second booster was into the vertebrates, and as such you can not only see that there’s an origin of complexity before the nervous system developed, but it actually was a precursor and required components for the nervous system.
 
This proto-synapse that you talk about, would it consist of about 250,000 billion synapses then, if human brains have about 1 million billion synapses?
 
I wouldn’t put it like that. What I would say was that the molecular architecture or organization, or proteins that are in these ancient synapse were the ones that first came from yeast where they were collectively involved with controlling response to the animal to its environment in various ways.
 
That same collective or set of proteins was recruited into synapses of the first neurons of invertebrates. And at the same time it had additional proteins added to it to make it [like a computer chip] and become more powerful and specialized.
 
This molecular evolution, by the way, predates the origins of nervous systems and it may be the first origins of the brain as we know it.
 
There are other elements to this story … and this is one of the fascinating puzzles. We calculated that the evolution of these big complex synapses found in the vertebrates happened before vertebrates evolved their really big brains with billions of nerve cells.
 
We wondered if all of these newly evolved synapse proteins could be doing something special in the big brains of mammals. So we did a protein profiling experiment where we looked into the different regions of the brain, places like cortex, hippocampus, spinal cord, we did them in the mouse.
 
We looked at the expression of a very large number of these proteins in many different parts of the brain, and found a very simple relationship. We found that those vertebrate innovations, or the newly evolved proteins, were preferentially used to make those parts of the brain specialized. In other words, the molecular evolution of synapses, this molecular complexity in that three-stage model [that I’ve been discussing], that was a basis and was used to make the specialized parts that are characteristic of mammals and other big-brained animals.
 
We think that the synapse evolution might have driven the differentiation of brain regions, and therefore we’ve uncovered two design principles. One is the ancestral origins and their multi-stage development, and the second is this sort of combinatorial usage of these proteins in the nervous systems of these animals to give different brain regions.
 
Appreciate for a moment if I said to you, ‘Look, I brought you a Lego kit for Christmas, and I [brought] a little Lego kit with not many different types of blocks and I [brought] you a different Lego kit which has a lot of big blocks in it.’
 
Clearly, you can make many more combinations of structures with the big kit. And that’s effectively what goes on in the nervous system of mammals. They can use this bigger molecular tool box made by the synapse proteome to construct many more combinations and varieties of synapses.
 
Does this process continue from generation to generation? Would the synapses of my grandparents and parents be very different from mine in complexity, for instance?
 
Our data doesn’t really address that kind of issue. … We are looking over a deep long range of evolution back to single-cell animals. The number of synapse proteins is in all of the different vertebrates … they’re all basically the same set of proteins. There’s no real difference in terms of the numbers.
 
The major difference is between invertebrates and vertebrates. That isn’t to say there aren’t fine structural changes in the individual proteins in the human evolution. There is evidence for that.
 
Is that something you’d be interested in looking at or even possible to look at?
 
Definitely, it’s possible to look at that. That work requires [doing] a proteomic experiment such that it allows us to use our proteomic data to drive a kind of genomic comparative data study.
 
On some level, do more proteins equal more brain power?
 
We think there’s good evidence to support that view. I’ll give you several lines of evidence. Amongst the strongest evidence is that if you compare genes that are in invertebrates with vertebrates, there are some gene families that have expanded and there are some quite nice examples, subunits of ion channels, for example, or other key adaptive proteins.
 
But in the invertebrate species, they may have only one protein or effectively one subunit of that type of molecule. But in the vertebrate species, they will have duplicated twice to produce four. And then what you discover, if you look at the function of those individual variants that occur in mammals by, say gene knock-out in a mouse, you discover that they result in particular kinds of phenotypes.
 
In other words, all of those four subunits have contributed to subtle and specific functions and invertebrates don’t have those, so they can’t have all those subtle and specific functions.
 
And then if you look at them in multi-protein complexes, imagine now you have a complex made of three proteins, and in an invertebrate you might only have a choice of for each of those three proteins just one gene encoding it. But if you have a vertebrate species where you have four genes for two of those proteins, you’re going to have sixteen different combinations.
 
So the combinatorial expansion is really an advantage for the mammals, and if you disrupt those genes, you can see specialized changes in behavior.
 
We believe that’s consistent with the following behavior: That the expansion in the synapse proteome has given those animals with expanded proteomes an expanded behavioral repertoire. And as I said earlier, we also have good evidence that it contributes to their regional differentiation of their nervous systems.
 
So we’re confident that this has given higher animals a higher range of behavior.
 
The other side of this is … there’s a disease element to this. While the benefit of having more synapse proteins is that it gives those animals a greater range of behaviors and specialized brain regions, there’s no free lunch because the cost of having these new genes is mental illness.
 
Some of these recently evolved genes went defective, produce autism, schizophrenia, or learning disability. … Vertebrates have evolved these extra genes and it’s terrific when those genes are working because now these animals can do all these wonderful behaviors, but if one of those genes is not working as a result of a mutation, you can end up with some severe behavioral consequences.

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