Contribution of A-to-I RNA editing, M6A RNA Methylation, and Alternative Splicing to physiological brain aging and neurodegenerative diseases

Neuroinflammation and Neurodegenerative Diseases: How Much Do We Still Not Know?

“…They appear to influence neuroinflammation. Among these, A-to-I RNA editing, m6A RNA methylation, and alternative splicing (AS) impact the neuronal cell life cycle, induce neuron death mechanisms, and contribute significantly to neuroinflammation and age-related neurodegeneration [17]. A-to-I RNA editing is a post-transcriptional mechanism modulating double-stranded (ds) RNA structures via the catalytic activity of adenosine-deaminase acting on RNA (ADAR) enzymes.…”

“…A-to-I RNA editing is a post-transcriptional mechanism modulating double-stranded (ds) RNA structures via the catalytic activity of adenosine-deaminase acting on RNA (ADAR) enzymes. It consists in the deamination of specific adenosine (A) into inosine (I) by altering both coding and non-coding transcripts [17]. Three ADAR enzymes are expressed in human cells-ADAR1, ADAR2 and ADAR3-and have high expression and activity in the brain in terms of regulating neurodevelopment, brain function, and physiological brain aging (widely quoted in [17]).…”

“…It consists in the deamination of specific adenosine (A) into inosine (I) by altering both coding and non-coding transcripts [17]. Three ADAR enzymes are expressed in human cells-ADAR1, ADAR2 and ADAR3-and have high expression and activity in the brain in terms of regulating neurodevelopment, brain function, and physiological brain aging (widely quoted in [17]). Consequently, the brain appears to be susceptible to ADAR activity and RNA-editing dysregulation, which potentially initiate CNS disorders, such as glioblastoma, epilepsy, and ND (widely quoted in [17]).…”

“…Altered expression of N6-methyladenosine (m6A), a dynamic and reversible posttranscriptional alteration adding a methyl group to the N6 position in selected adenosines of each type of RNA [17], has been documented in aging mouse and human brains. In terms of ND, unusual m6A alterations have been identified in AD, PD, and ALS.…”

“…Furthermore, it is emerging that neuroinflammation is also the result of the modulation in expression of genes encoding immune and injury's molecules. miRNAs [15] and epigenetic factors [16], including A-to-I RNA editing, M6A RNA methylation, and alternative splicing [15][16][17], have recently been revealed to have a fundamental role. Finally, circadian rhythm disorders have recently also been discovered to impact both the onset and development of neuroinflammation through the activation of glial cells and peripheral immune responses [18].…”