RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

Abstract

The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on the dynamic nature and spatiotemporal patterning of gene expression. These features of gene expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, and non-coding RNA activity, amongst others. In concert, another regulatory layer by which RNA bases and sugar residues are chemically modified enhances neuronal transcriptome complexity. Similar RNA modifications in other systems collectively constitute the cellular epitranscriptome that integrates and impacts various physiological processes. The epitranscriptome is dynamic and is reshaped constantly to regulate vital processes such as development, differentiation and stress responses. Perturbations of the epitranscriptome can lead to various pathogenic conditions, including cancer, cardiovascular abnormalities and neurological diseases. Recent advances in next-generation sequencing technologies have enabled us to identify and locate modified bases/sugars on different RNA species. These RNA modifications modulate the stability, transport and, most importantly, translation of RNA. In this review, we discuss the formation and functions of some frequently observed RNA modifications-including methylations of adenine and cytosine bases, and isomerization of uridine to pseudouridine-at various layers of RNA metabolism, together with their contributions to abnormal physiological conditions that can lead to various neurodevelopmental and neurological disorders.

Keywords: RNA metabolism; RNA modifications; brain development; neurodegenerative diseases; neurodevelopmental disorders.

Figure 1

Illustrative model summarizing how various RNA metabolic processes are modulated by RNA modifications. Different RNA modifications, e.g., m6A, m5C, m1A, A-to-I RNA editing and pseudouridine, are represented by blue, purple, yellow, red and yellow colored pins, respectively. Various mechanisms of activation or inhibition of RNA metabolisms by RNA modifications are represented by (1) to (12), e.g., m6A modifications of pre-mRNAs (1) and miRNAs (2) facilitate splicing and miRNA biogenesis, respectively. The model shows that m6A modification of the 3′-UTR of mRNAs facilitates binding of miRNAs to this region and inhibits mRNA transport/translation (3). VERMA-mediated m6A modification near the 3′-UTR and stop codons of mRNAs facilitates alternative polyadenylation (4). Alternatively, m6A modification near the 3′-UTR and stop codons causes de-adenylase binding, thereby impairing stability (5). De-capping at the 5′-cap site with nearby m6A inhibits translation initiation and also reduces mRNA stability as a result of endonuclease activity (6). m5C modification of tRNAs induces their cleavage, thus altering RNA stability (7). Accumulations of cleaved tRNA fragments induce oxidative stress, which inhibits cellular translation (8). m1A modification impairs base pairing of tRNA-anticodons with the mRNA initiation codon, inhibiting translation initiation (9). Both A-to-I editing and pseudouridine modification alter start or stop codons of mRNAs, blocking mRNA transport/translation (10, 11, 12).