Recently, researchers have used advanced microscopy to investigate the role that RNA modifications play in ‘synaptic tagging’ within the brain.
Synaptic plasticity is the term used to describe changes that occur at the junctions between neurons and allows them to communicate. The idea that synapses could change, depending on how active or inactive they are, was first proposed by Donald Hebb in 1949. Today, synaptic plasticity is widely accepted as the main neural basis of learning and memory.
Synaptic plasticity processes involve changes in synaptic strength. They require mRNA to be transcribed in the nucleus and locally translated at dendritic sites. It is thought that RNAs are available at specific activated synapses due to ‘synaptic tagging’. However, what constitutes a ‘synaptic tag’ remains unclear. It has been proposed that RNA regulation, RNA degradation and protein translation may play key roles in this process.
What is N6-methyladenosine (m6A)?
N6-methyladenosine (m6A) is a highly abundant and reversible mRNA modification in eukaryotes. It is the most conserved post-translational modification and is found in a wide range of cellular RNAs. m6A is facilitated by ‘writers’ (methyltransferases), ‘erasers’ (demethylases) and ‘readers’ (m6A-binding proteins). Demethylases, such as AlkB homolog 5 (ALKBH5), remove m6A methylation groups from RNA. Whereas m6A-binding proteins are enzymes that bind to the m6A methylation site and play a role in gene expression, including for YT521-B homology domain family proteins (YTHDFs).
YTHDFs, such as YTHDF1, YTHDF2 and YTHDF3 proteins, recognise m6A modifications on target RNAs and subsequently direct different complexes to regulate RNA signalling pathways. Therefore, it is believed that their function is to regulate m6A dependent mRNA stability and translation. However, the exact role of individual m6A ‘erasers’ and ‘readers’ in subcellular structures is still largely unknown.
Studying RNA modifications in the brain
Recently, researchers from the University of Nottingham used advanced microscopy to investigate the role that m6A methylation plays in ‘synaptic tagging’ in the brain. The findings, which were published in Molecular Psychiatry, are hoped to enhance scientists understanding of how neurological cells communicate as well as help to identify new treatments for neurodegenerative or psychiatric conditions.
The team directly investigated the relationships between m6A modifications and YTHDF1 and YTHDF3 readers, along with ALKBH5 erasers, within brain synapses. They found that m6A demethylation by ALKBH5 occured at active synapses during short term plasticity. However, only the YTHDF1 and YTHDF3 readers showed high co-localisation to modified RNAs during late-stage plasticity.
Additionally, the researchers conducted m6A-sequencing of human parahippocampal grey and white matter tissue. The parahippocampus is a large portion of the medial temporal lobe that is essential for memory formation. They also sequenced foetal brain tissue 20-33 weeks after conception. This analysis revealed enriched m6A in 5,298 coding transcripts in grey matter tissue, 6,968 coding transcripts in white matter tissue and 6,730 coding transcripts in foetal brain tissue. The most enriched m6A binding motif was found to be GGAC.
RNA modifications in reversible brain disease states
Overall, these findings support that m6A demethylation by ALKBH5 is a crucial component of the ‘synaptic tagging’ process and could be responsible for alterations that lead to synaptic dysfunction and reversible disease states. Additionally, this research has revealed that the involvement of effector proteins, such as YTHDF1 and YTHDF3, differ between short- and long-term plasticity phases, and throughout brain maturation. Therefore, research on cognitive disorders that currently assess m6A-binding proteins as pharmacological targets should consider these temporal changes during drug development.
Essentially, this research has highlighted that m6A regulated processes potentially contribute to disease pathologies or brain states, such as addiction disorders or mental health conditions. But further investigations will be required to understand exactly how much these modifications are responsible, and whether it is feasible to be reverse them through new therapies.
Dr Helen Knight, from the University of Nottingham and leader of the study, explained:
“In this new study, we are able to gain a new understanding of the genomic mechanisms which regulate how nerve cells communicate at synapses. These genomic mechanisms involve methyl groups being put on RNA messages and importantly taken off when a synapse is active. The implications are very important for normal brain function but also for reversible psychiatric mental conditions such as anxiety and addiction disorders and early-stage neurodegenerative diseases such as dementias.”
Image credit: The Guardian
