Surprise: A virus-like protein is important for cognition and memory

January 11, 2018, University of Utah
A protein involved in cognition and long-term memory, called Arc, acts like a protein from viruses. Arc can encapsulate and deliver its own genetic material to brain cells (neurons) similar to the way viruses infect host cells. This picture shows neurons that have taken up Arc and are expressing the genetic material stored within it. Credit: Elissa Pastuzyn

A protein involved in cognition and storing long-term memories looks and acts like a protein from viruses. The protein, called Arc, has properties similar to those that viruses use for infecting host cells, and originated from a chance evolutionary event that occurred hundreds of millions of years ago.

The prospect that virus-like proteins could be the basis for a novel form of cell-to-cell communication in the brain could change our understanding of how memories are made, according to Jason Shepherd, Ph.D., a neuroscientist at University of Utah Health and senior author of the study publishing in Cell on Jan. 11.

Shepherd first suspected that something was different about Arc when his colleagues captured an image of the protein showing that Arc was assembling into large structures. With a shape that resembles a capsule from a lunar lander, these structures looked a lot like the retrovirus, HIV.

"At the time, we didn't know much about the molecular function or evolutionary history of Arc," says Shepherd who has researched the protein for 15 years. "I had almost lost interest in the protein, to be honest. After seeing the capsids, we knew we were onto something interesting."

The gap in research was not for want of an interesting subject. Prior work had shown that mice lacking Arc forgot things they had learned a mere 24 hours earlier. Further, their brains lacked plasticity. There is a window of time early in life when the brain is like a sponge, easily soaking up new knowledge and skills. Without Arc, the window never opens.

Scientists had never considered that mechanisms responsible for acquiring knowledge could stem from foreign origins. Now, the work by Shepherd and his team has raised this intriguing possibility.

A protein important for cognition and memory named Arc can encapsulates genetic material (polyhedron enveloping the ribbon-like strands) and delivers it to brain cells in a manner similar to the way in which viruses infect host cells. Credit: Chris Manfre
Everything Old is New Again

Seeing Arc's unusual propensity to form virus-like structures prompted Shepherd to scrutinize the protein sequence with a new set of eyes. He found that regions of the code were similar to that from viral capsids. An essential tool for viral infection, capsids carry virus' genetic information and deliver it from cell to cell in its victim.

Given that Arc looks like a viral protein, Shepherd and his colleagues designed a set of experiments to test whether it also acts like one. They first determined that several copies of Arc self-assemble into hollow virus-like capsids and stash its own genetic material, in this case mRNA, inside them. When the scientists added the capsids to mouse brain cells, or neurons, growing in a dish, Arc transferred its genetic cargo into the cells.

After viruses invade host , they emerge ready to infect once again. It appears that Arc works in a similar way. The scientists gathered Arc that had been released from mouse neurons and determined that the proteins and their cargo could be taken up by another set of neurons. Unlike for viruses, activating neurons mobilizes Arc, triggering the release of capsids.

"We went into this line of research knowing that Arc was special in many ways, but when we discovered that Arc was able to mediate cell-to-cell transport of RNA, we were floored," says the study's lead author, postdoctoral fellow Elissa Pastuzyn, Ph.D. "No other non-viral protein that we know of acts in this way."

A protein involved in cognition and storing long-term memories looks and acts like a protein from viruses, according to research by scientists at University of Utah Health. The protein, called Arc, has properties similar to those that viruses use for infecting host cells and could be the basis for a novel form of communication in the brain. Credit: Jacobo Lopez, Yi-Chu Su, Hugo Vaca
When Lightning Strikes Twice

The story of Arc's origin is relayed through the genomes of animals throughout evolutionary time. 350-400 million years ago, a chance occurrence struck four-limbed creatures that roamed the earth. An ancestor to retroviruses, called retrotransposons, inserted its into the animals' DNA. The event led to the mammalian Arc that we know today.

The significance of such an event is hinted at by the fact that it happened more than once. An accompanying paper in the same issue of Cell shows that a version of Arc found in flies also looks and acts like a viral capsid. Vivian Budnik's lab at the University of Massachusetts shows that fly Arc transports RNA from neurons to muscles to control movement. Even though mammalian and fly Arc evolved from the same class of retrotransposons, the event in flies occurred about 150 million years later.

"As an evolutionary biologist this is what is the most exciting to me," says co-author Cédric Feschotte, Ph.D. a professor at Cornell University. "The fact that it happened at least twice makes us think that it happened even more."

Shepherd believes this could mean that it is advantageous to have this viral-inspired system in place, and it may represent a novel form of intercellular communication. This hypothesis remains to be tested in mammals. "Knowing what cargo Arc vesicles transport in living animals will be critical to understanding the function of this pathway," he says.

Remember the unusual viral-like that you just learned about? It could be controlling your memory.

Explore further: Scientists find the invisibility cloak that shields HIV-1 from the immune system

More information: Cell (2018). DOI: 10.1016/j.cell.2017.12.024 , http://www.cell.com/cell/fulltext/S0092-8674(17)31504-0

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8 comments

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UKCatFan
5 / 5 (1) Jan 11, 2018
If mammalian advanced memory could stem from a chance encounter with a virus millions of years ago, what implications does that have on our chances of detecting intelligent life in the universe? Did the Drake Equation just get another limiting variable?
betterexists
not rated yet Jan 11, 2018
Good Report. Why Visit Other Celestial locations? Why NOT Collect ALL PROTEINS on this Earth from ALL Organisms first ? 20,000 human Protein-coding genes. Total number of proteins in human body is estimated to be around 50,000(http://www.innova...an-body) AND Yesterday Count Report was 4.2M Proteins/Human Cell.
betterexists
1 / 5 (3) Jan 11, 2018
Dogs Too have Memory. They can Remember their owners, Not just their Smell Alone ! If We can stop that specific protein production in dog brains, WHAT HAPPENS?
Ducks etc., have many babies. Can they remember all of them AFTER THE Eggs are Hatched ? Can you replace one with other ? Is it possible to stick your arm through a hole and see if your pitbull will bite it or not ?
betterexists
not rated yet Jan 11, 2018
Is it possible to stick your arm through a hole and see if your pit bull will bite it or not ?
It was just a joke. Any how, Try to use the Services of this Transporting-cum-Encapsulating Arc Protein to the Fullest Extent elsewhere in the Bodies in novel ways, if you can !
jloohunret
5 / 5 (2) Jan 11, 2018
This article proves how much we don't know about the brain.
thingumbobesquire
not rated yet Jan 12, 2018
Protein dynamics and the Riemannian surface function: http://thingumbob...ace.html
antialias_physorg
5 / 5 (2) Jan 12, 2018
"If mammalian advanced memory could stem from a chance encounter with a virus millions of years ago, what implications does that have on our chances of detecting intelligent life in the universe?"

Since it was a singular event you can't base any predictions on the probability of it happening elsewhere. All a singular event tells you is: "it's not impossible".

"Did the Drake Equation just get another limiting variable? "

The Drake equation was a humorous way of formulating an agenda for a conference (an informal SETI conference held at the Green Bank observatory in 1961). It just listed stuff together (like various factors that might or might not be relevant to SETI) that they wanted to discuss.
It was never meant to be a serious equation - don't treat it as such
johnhew
not rated yet Jan 12, 2018
Drake's equation was used circumnavigate the globe

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