Brains of the living and the dead do not read important genes in the same way: ScienceAlert

Death is, to say the least, a pretty unpleasant event for a living brain. The cascade of effects that occurs when oxygen disappears washes over the way our cells transcribe and translate our DNA, desperately trying to keep the lights on.

A comparison of post-mortem brain tissue and samples from living patients has revealed for the first time significant differences in the way RNA strands are modified. This opens up new potential targets for the diagnosis and treatment of diseases.

Researchers at the Icahn School of Medicine at Mount Sinai in New York focused on the way in which certain base codes of adenosine (A) in messenger RNA are exchanged for a completely different base, inosine (I).

“Until now, the investigation of A-to-I editing and its biological significance in the mammalian brain has been limited to the analysis of postmortem tissue,” says genomicist Michael Breen.

“By using fresh samples from living individuals, we were able to uncover significant differences in RNA editing activity that may have been missed in previous studies that relied only on postmortem samples.”

To turn the genes encoded by double-stranded DNA helixes into functional proteins, biology must copy their sequences into a slightly different format that relies on RNA instead. These “messengers” can then be translated into proteins by other RNA structures that carry the amino acid building blocks with them.

Billions of years of evolution have taken advantage of this intermediary of transcription and translation to add, in effect, a whole new library of proteins. Like a dishonest editor who rewrites manuscripts to serve entirely new purposes, cells can adapt a gene’s messenger RNA to serve entirely different purposes.

Some species, particularly cephalopods, take RNA editing to a whole new level by rewriting their brains’ genetic instructions as needed.

In vertebrates like us, the removal of an amino group, or “deamination,” from adenosine converts it to inosine, a base similar to guanine (G). This usually produces a very different end product than the one encoded in the DNA gene library.

This A-to-I base exchange is accomplished by the RNA-acting adenosine deaminase (ADAR) family of enzymes, which play a crucial role in the formation of a variety of tissues, including those in the brain.

In fact, the process is so critical that editing errors can lead to a variety of neurological disorders. To determine exactly how edits to certain transcribed genes develop into life-threatening conditions, researchers analyzed postmortem samples.

As convenient as collecting these samples may be, they have one major disadvantage.

“We hypothesized that molecular responses to postmortem-induced hypoxic and immunological reactions can significantly alter the landscape of A-to-I editing,” says the study’s lead author, Miguel Rodríguez de los Santos, a molecular biologist at Mount Sinai.

“This can lead to misunderstandings about RNA editing in the brain if we only study postmortem tissues.”

In fact, samples of brain tissue from living patients obtained during surgical placement of deep brain stimulation electrodes showed large differences in the activity of two types of ADAR enzymes and in the sites at which they acted.

The team’s analysis found that A-to-I editing occurred more frequently at over 72,000 sites on RNA strands in samples from recently deceased patients than in samples from living patients.

However, there were hundreds of sites where the opposite was true, but where the editing process was more pronounced in the living brain samples. While some of the sites had known functions in brain plasticity, many require further investigation to understand the underlying mechanisms.

“It is important to emphasize that our findings do not refute the use of postmortem brain tissue in the study of A-to-I regulation, but rather provide the missing context for it,” says co-senior author Alexander Charney, a physician and scientist at Mount Sinai.

“Understanding these differences will help improve our knowledge of brain function and disease through the lens of RNA editing modifications, potentially leading to better diagnostic and therapeutic approaches.”

This research was published in Nature communication.