It's extremely difficult to study the inner workings of the human brain, and researchers who seek to do so usually rely on postmortem samples that have been donated by volunteers. But a new study has suggested that these samples could represent something that is very different from typical brain function. In this work, researchers determined that live and postmortem tissues from a part of the brain called the prefrontal cortex are significantly different. The differences involve a change made to RNA molecules in which adenosine is modified to inosine, one of the most common medications in the brain. The findings, which may have major implications for brain disease diagnostic tools and therapeutics, have been reported in Nature Communications.
Active genes are transcribed into messenger RNA (mRNA) molecules, and those mRNA molecules can be subjected to many modifications before they are translated into proteins. Post-translational modifications are common, and can have a major impact on how mRNA is used. Enzymes called Adenosine Deaminases that Act on RNA (ADARs) are crucial to RNA modifications; they perform the conversion of adenosines (As) to inosines (Is). This process is known as RNA editing and this can continue after death.
There are thousands of places where As are converted to Is by these enzymes in various cells. This process is known to be related to the development of the brain and maturation of neurons. There are certain neurological disorders in which A-to-I editing is disrupted.
"Until now, the investigation of A-to-I editing and its biological significance in the mammalian brain has been restricted to the analysis of postmortem tissues. By using fresh samples from living individuals, we were able to uncover significant differences in RNA editing activity that previous studies, relying only on postmortem samples, may have overlooked," said co-senior study author Michael Breen, PhD, an Assistant Professor at Icahn School of Medicine at Mount Sinai.
"We were particularly surprised to find that RNA editing levels were significantly higher in postmortem brain tissue compared to living tissue, which is likely due to postmortem changes such as inflammation and hypoxia that do not occur in living brains." The RNA editing that happens in living cells is also usually quite important to cell function. Some of these sites are known to be dysregulated in human disease, emphasizing the importance of studying postmortem as well as living samples.
The brain is not supplied with oxygen after death, which causes rapid, irreversible damage to brain cells, which can also affect ADARs and A-to-I editing.
This work is related to the Living Brain Project, which utilizes brain tissue from living donors who are undergoing neurosurgical procedures. It has highlighted the importance of using reliable samples to study basic biology.
