New Insights on the Role of N6-Methyladenosine RNA Methylation in the Physiology and Pathology of the Nervous System

Abstract

RNA modifications termed epitranscriptomics represent an additional layer of gene regulation similar to epigenetic mechanisms operating on DNA. The dynamic nature and the increasing number of RNA modifications offer new opportunities for a rapid fine-tuning of gene expression in response to specific environmental cues. In cooperation with a diverse and versatile set of effector proteins that “recognize” them, these RNA modifications have the ability to mediate and control diverse fundamental cellular functions, such as pre-mRNA splicing, nuclear export, stability, and translation. N 6 -methyladenosine (m 6 A) is the most abundant of these RNA modifications, particularly in the nervous system, where recent studies have highlighted it as an important post-transcriptional regulator of physiological functions from development to synaptic plasticity, learning and memory. Here we review recent findings surrounding the role of m 6 A modification in regulating physiological responses of the mammalian nervous system and we discuss its emerging role in pathological conditions such as neuropsychiatric and neurodegenerative disorders.

NSun2 deficiency promotes tau hyperphosphorylation and neurodegeneration through epitranscriptomic regulation of miR-125b

“…Our results confirm that NSun2, one of the best described RNA methyltransferases in higher eukaryotes 56-, is expressed in the adult human brains (Figure 1). However, current understanding of the role that epitranscriptomic regulation plays in brain function and dysfunction is limited [63][64][65] . NSun2 deficiency has a negative impact on learning and memory in fruit flies and causes intellectual disability and neurological abnormalities in humans 62,66 .…”

“…To date, several studies have implicated epitranscriptomic regulation of coding and non-coding RNA in diverse biological functions 65,70 . Here, we show NSun2 RNA methyltransferase protein levels are decreased in AD brains, denoting epitranscriptomic alterations in the AD process (Figure 1).…”

Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

“…A genome-wide association study (GWAS) revealed that m6A dysfunction is linked to developing neurological disorders [107]. Furthermore, several studies have confirmed the role of m6A modification in the development of these disorders [108,109]. Altered m6A regulation could play an important role in the occurrence of Alzheimer's disease and its associated dementia [110,111].…”

Emerging Role of m6 A Methylome in Brain Development: Implications for Neurological Disorders and Potential Treatment

“…The developing and adult brain is characterized by the outgrowth of dendrites and axons of neurons known to form neural connections called synapses. Interestingly, synapses are enriched with m 6 A, which modulates dendrite formation (dendritogenesis), axonogenesis, and synaptic growth (synaptogenesis) and activity (reviewed in Li et al, 2019 ; Dermentzaki and Lotti, 2020 ). m 6 A-based transcriptome profiling of the mouse brain (cortex and cerebellum) showed enrichment of m 6 A modification linked to dendrite and dendritic spine, axon and axon guidance, and synaptogenesis and synaptic transmission ( Chang et al, 2017 ).…”

“…The massive prevalence of m 6 A in the developing and postnatal brain signifies the importance of m 6 A modification in regulating brain morphogenesis and function. Indeed, a chunk of the expanding knowledge indicating the phenomenal role of m 6 A in orchestrating neural development and function includes the proliferation of neural stem cells (NSCs) and other neural precursor cells, neuroprogenitor cell differentiation, gliogenesis, elaboration of neural processes, and synaptic transmission (reviewed in Widagdo and Anggono, 2018 ; Li et al, 2019 ; Chokkalla et al, 2020 ; Dermentzaki and Lotti, 2020 ; Livneh et al, 2020 ).…”