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.

Multivariate Analysis of RNA Chemistry Marks Uncovers Epitranscriptomics-Based Biomarker Signature for Adult Diffuse Glioma Diagnostics

“…Recently, chemical modifications of RNA (a.k.a. epitranscriptomics) emerged as a novel layer of gene expression regulation in healthy tissues (e.g., brain), as well as in several pathologies such as neurodegenerative diseases 7 and cancer. 8 , 9 In particular, we and others associated several chemical marks with cancer evolution, adaptation, as well as the response to conventional therapy.…”

A C-Terminally Truncated TDP-43 Splice Isoform Exhibits Neuronal Specific Cytoplasmic Aggregation and Contributes to TDP-43 Pathology in ALS

“…RT-PCR demonstrated that TDP43C-spl was expressed in human spinal cord, brain tissue and DRG. This may be explained by the fact that, like other alternatively spliced genes, the differential expression of the various TDP-43 isoforms may be regulated by the interplay of cis elements and trans factors that exhibit cell type specificities (Chatterjee et al, 2021 ).…”

Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1

“…In this regard, m6A modifications have been shown to play a role in different processes including learning memory, neurogenesis, and axon regeneration. The dysregulation of m6A pathways has been implicated in the onset of neurological diseases including AD, where m6A modifications at the 3′-UTR of mRNAs alters the translation of transcripts linked to age-related disease phenotypes [ 20 ]. In accordance, recent evidence showed a progressive m6A increase concomitantly with AD severity in human brains.…”