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How octopuses beat brain freeze

Rewriting messenger RNA changes neuron protein structures in the cold

by Laurel Oldach
June 8, 2023 | A version of this story appeared in Volume 101, Issue 19

A photo of an octopus
Credit: Tom Kleindinst/Woods Hole Oceanographic Institute

Octopuses make dazzling use of camouflage, quickly changing their skin color as they move through various environments. New research suggests that another, less visible response to the environment may help keep their brains capable of this and other feats. By editing messenger RNA (mRNA) in response to changing temperatures, the cephalopods can rewrite their protein sequences on the fly, altering how important proteins in the nervous system work (Cell 2023, DOI: 10.1016/j.cell.2023.05.004).

Many animals can edit their RNA by converting an adenosine base encoded into it by DNA to an inosine—but such edits usually do not happen in protein-coding regions. Researchers at Woods Hole Marine Biological Lab and Tel Aviv University surprised colleagues when they reported that cephalopods use RNA editing to recode thousands of proteins (eLife 2015, DOI: 10.7554/eLife.05198). The current study began when the team asked, “What is this good for?” says colead Eli Eisenberg.

Reaction scheme showing deamination of adenosine to inosine.
Adenosine deaminase acting on RNA (ADAR) enzymes convert adenosine to inosine in RNA. Because inosine can mimic guanosine, editing can affect which amino acid is incorporated into a protein.

Better response to temperature changes was an obvious hypothesis, because cold-blooded marine animals like the octopus are particularly vulnerable to the effects of varying temperatures on their biochemistry. In a prior study, colead author Joshua Rosenthal’s lab had found that different octopus species edit an ion-channel mRNA at frequencies correlated with water temperature (Science 2012, DOI: 10.1126/science.1212795).

To find out whether temperature affects RNA editing in the short term, the researchers sequenced RNA from the nervous systems of captive octopuses from a single species and found that about 3,600 mRNAs were more heavily edited in cold than in warm water. The editing responded to changes in the environment; gradually raising or lowering a tank’s temperature could change editing frequency within hours.

Many of the edited RNAs encode proteins important in the nervous system, and the researchers found that edits could change the proteins’ structures and activity. An edited version of kinesin, which moves cargo through neurons, moved at a more consistent—albeit slower—pace in the cold. And an edited synaptotagmin, which is involved in releasing neurotransmitters from synapses, binds calcium differently than the version in the genome.

“The effect looks modest, but in most synapses . . . small changes in Ca2+ affinity can have large effects on [neurotransmitter] release,” writes synaptotagmin expert Edwin Chapman of the University of Wisconsin-Madison, who was not involved in the study. “So this could be a way to tune the Ca2+ requirements for synaptic transmission—absolutely fascinating!”

Whether the edit affects neuron physiology remains to be tested. The researchers are still trying to work out exactly how editing gets turned up so much, and how the cumulative effects of thousands of subtle tweaks might help octopuses acclimate to cold water.

Stanford geneticist Jin Billy Li, who did not work on this study, called it “great work,” but said he hopes to see a follow-up. “Ideally, you want to show some editing events are really functional physiologically. But that’s a very difficult question to ask—perhaps not even possible.”

“It’s a new mechanism for thermal acclimation that I haven’t come across before,” says Fredrik Jutfelt of the Norwegian University of Science and Technology, who studies fish physiology and temperature change. “This is kind of a proof of concept, and then we have to dig into the mechanism.”


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