Researchers have found major disparities between postmortem and living prefrontal cortex brain tissues regarding a prevalent RNA modification known as adenosine-to-inosine (A-to-I) editing.
Researchers from the Icahn School of Medicine at Mount Sinai have provided insights into the complex functions and precise regulatory mechanisms of RNA editing, a crucial process crucial for brain function and health.
In a recent study published in Nature Communications on June 26, researchers highlighted significant variances in A-to-I editing between postmortem and living prefrontal cortex brain tissues. This discovery is anticipated to influence the development of diagnostic tools and treatments for brain disorders.
While DNA contains genetic instructions, RNA is responsible for carrying out these instructions to create functional proteins that govern various bodily functions, particularly in the central nervous system. RNA’s function and stability are regulated by multiple modifications, including RNA editing, which is a continuous process carried out by enzymes like ADAR in all cells and tissues, even after an individual’s death.
The conversion of adenosine to inosine (A-to-I) is a well-studied RNA modification critical for brain function and is regulated by proteins such as ADAR1 and ADAR2. In the mammalian brain, numerous A-to-I editing sites have been identified across different brain regions and cell types, some of which were discovered by Mount Sinai researchers. These sites contribute to neuronal development and brain maturation and their dysregulation has been linked to neurological conditions.
Lead study author, Michael Breen, PhD, highlighted the significance of investigating A-to-I editing in living brain tissue, as differences were observed in editing activity compared to postmortem samples. The higher levels of RNA editing in postmortem brain tissues can be attributed to postmortem changes like inflammation and hypoxia absent in living brains. The study emphasizes the importance of studying both living and postmortem brain tissues for a comprehensive understanding of brain biology.
Postmortem changes in brain tissue due to oxygen deprivation post-death can lead to alterations in ADAR expression and A-to-I editing. This underscores the necessity of studying living brain tissue to obtain a clear understanding of RNA editing in the human brain.
A research project centered on the Living Brain Project provided fresh dorsolateral prefrontal cortex (DLPFC) tissues from living individuals undergoing deep brain stimulation for neurological conditions. Postmortem DLPFC tissues were collected for comparison, allowing for an in-depth analysis of genomic data types.
The study revealed over 72,000 locations with differing A-to-I editing patterns in postmortem versus living DLPFC brain tissues. Higher levels of ADAR enzymes were observed in postmortem brain tissues, leading to elevated editing patterns. Notably, numerous sites showed increased A-to-I editing in living brain tissues, particularly in synaptic connections, suggesting their crucial role in brain function and activity.
Critical A-to-I editing sites in living brains were found to be heavily edited, indicating involvement in essential neuronal processes like synaptic plasticity essential for learning and memory. However, many other editing sites in living brain tissues require further investigation to understand their impact on brain health.
The study authors emphasize the importance of utilizing living brain tissue alongside postmortem samples to gain more accurate insights into A-to-I editing in the human brain. This knowledge could enhance diagnostic and therapeutic strategies for brain diseases.
The research team plans to delve deeper into the implications of RNA editing data, particularly in identifying therapeutic targets for Parkinson’s disease. Their ongoing research from the Living Brain Project aims to explore gene expression, proteomics, and multi-omics to gain a comprehensive understanding of the living brain.
Collaborating through the Living Brain Project, researchers aim to leverage deep brain stimulation as a platform for cutting-edge insights into human brain biology, potentially leading to new therapeutic avenues for brain disorders.
