Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma

Abstract

Despite a long history of research, neurodegenerative diseases and malignant brain tumor gliomas are both considered incurable, facing challenges in the development of treatments. Recent evidence suggests that RNA modifications, previously considered as static components of intracellular RNAs, are in fact dynamically regulated across various RNA species in cells and play a critical role in major biological processes in the nervous system. Innovations in next-generation sequencing have enabled the accurate detection of modifications on bases and sugars within various RNA molecules. These RNA modifications influence the stability and transportation of RNA, and crucially affect its translation. This review delves into existing knowledge on RNA modifications to offer a comprehensive inventory of these modifications across different RNA species. The detailed regulatory functions and roles of RNA modifications within the nervous system are discussed with a focus on neurodegenerative diseases and gliomas. This article presents a comprehensive overview of the fundamental mechanisms and emerging roles of RNA modifications in these diseases, which can facilitate the creation of innovative diagnostics and therapeutics for these conditions.

Keywords: RNA modifications; glioma; neurodegeneration.

Figure 1

RNA modifications in various neurological diseases. Epitranscriptomic RNA modifications in both mRNA and different non-coding RNAs are involved in multiple types of neurologic disorders. Genetic analysis and animal model studies have revealed that various RNA modifications and their machineries have critical roles in the etiology of neurodegenerative diseases and gliomas. mRNA: messenger RNA; rRNA: ribosomal RNA; lncRNA: long non-coding RNA; tRNA: transfer RNA; circRNA: circular RNA; UTR: untranslated region; A-to-I editing: adenosine to inosine RNA editing.

Figure 2

m6A RNA modification and its regulatory proteins in glioma pathogenesis. The m6A RNA modification pathways implied for glioma pathogenesis involve various nuclear and cytoplasmic processes in the cells. The ‘writers’ of the m6A mark, which include METTL3, METTL14, WTAP, RBM15, ZC3H13, and KIAA1429/VIRMA, collectively form the methyltransferase complex in the nucleus, utilizing SAM as a methyl donor to catalyze mRNA methylation. Conversely, ‘erasers’ such as FTO and ALKBH5 demethylate m6A-mRNA, reversing the modifications introduced by the writers. Within the cytoplasm, ‘readers’ such as YTHDFs, YTHDC2, HNRNPC, and the IGF2BP family recognize and bind to m6A-mRNA, affecting its stability, nuclear export, splicing, and translation. The involvement of IGF2BPs indicates their role in stabilizing m6A-mRNA, which is crucial for regulating gene expression that is vital for glioma progression. Furthermore, proteins like HNRNPs and eIF3 are implicated in splicing and translation, underscoring the complexity and importance of the m6A modification system in glioma pathogenesis. METTL3: Methyltransferase Like 3; METTL14: Methyltransferase Like 14; WTAP: Wilms’ Tumor 1-Associating Protein; RBM15: RNA Binding Motif Protein 15; ZC3H13: Zinc Finger CCCH-Type Containing 13; KIAA1429/VIRMA: Vir Like m6A Methyltransferase Associated; SAM: S-adenosylmethionine; FTO: Fat Mass and Obesity-Associated Protein; ALKBH5: AlkB Homolog 5; YTHDF: YTH Domain Family; YTHDC: YTH Domain Containing; HNRNP: Heterogeneous Nuclear Ribonucleoprotein; IGF2BP: Insulin-like Growth Factor 2 mRNA-Binding Proteins; eIF3: Eukaryotic Translation Initiation Factor 3.