Investigation into the role of methylation of the adenosine base (m6A) of RNA has only recently begun, but it quickly became apparent that m6A is able to control and fine-tune many aspects of mRNA, from splicing to translation. The ability of m6A to regulate translation distally, away from traditional sites near the nucleus, quickly caught the eye of neuroscientists because of implications for selective protein translation at synapses. Work in the brain has demonstrated how m6A is functionally required for many neuronal functions, but two in particular are covered at length here: The role of m6A in 1) neuron development; and 2) memory formation. The purpose of this review is not to cover all data about m6A in the brain. Instead, this review will focus on connecting mechanisms of m6A function in neuron development, with m6A's known function in memory formation. We will introduce the concept of "translational priming" and discuss how current data fit into this model, then speculate how m6A-mediated translational priming during memory consolidation can regulate learning and memory locally at the synapse.

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An Emerging Role of m6A in Memory: A Case for Translational Priming

Autophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

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

RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.

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A mark of disease: how mRNA modifications shape genetic and acquired pathologies.

RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N6-methyladenosine (m6A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m6A, how this influences neuronal development and function and how aberrant m6A signaling may contribute to neurological disease. M6A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m6A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m6A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m6A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m6A, although there in vivo activity and the dynamic nature of this modification requires further study. M6A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m6A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m6A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.

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Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

RNA modifications, in particular N6-methyladenosine (m6A), participate in every stages of RNA metabolism and play diverse roles in essential biological processes and disease pathogenesis Thanks to the advances in sequencing technology, tens of thousands of RNA modification sites can be identified in a typical high-throughput experiment; however, it remains a major challenge to decipher the functional relevance of these sites, such as, affecting alternative splicing, regulation circuit in essential biological processes or association to diseases As the focus of RNA epigenetics gradually shifts from site discovery to functional studies, we review here recent progress in functional annotation and prediction of RNA modification sites from a bioinformatics perspective The review covers naive annotation with associated biological events, eg, single nucleotide polymorphism (SNP), RNA binding protein (RBP) and alternative splicing, prediction of key sites and their regulatory functions, inference of disease association, and mining the diagnosis and prognosis value of RNA modification regulators We further discussed the limitations of existing approaches and some future perspectives

Recent advances in functional annotation and prediction of the epitranscriptome.

Genome-wide identification of m6A-associated single-nucleotide polymorphisms in Parkinson's disease.

Background Recently, the neurite outgrowth inhibitor-B (Nogo-B) receptor has been reported as a novel candidate gene for Parkinson's disease (PD). Nogo-B receptors need to combine with soluble Nogo-B to exert their physiological function. However, little is known about the relationship between serum soluble Nogo-B and PD. Methods Serum levels of sNogo-B and α-Synuclein (α-Syn) were measured in a cohort of 53 patients with PD and 49 healthy controls with the ELISA kit method. Results Serum sNogo-B level is significantly lower in the PD group than that in healthy controls and is negatively correlated with UPDRS-III score (p = 0.049), H&Y stage (p = 0.0108) as well as serum α-Syn level (p = 0.0001). The area under the curve (AUC) of serum sNogo-B in differentiating patients with PD from controls was 0.801 while the AUC of serum α-Syn was 0.93. Combining serum sNogo-B and α-Syn in differentiating patients with PD from HC presented higher discriminatory potential (AUC = 0.9534). Conclusion Decreased serum sNogo-B may be a potential biomarker for PD. Lower Nogo-B level reflects worse motor function and disease progression of PD. Serum sNogo-B is of added value to serum α-Syn panel in distinguishing PD from controls. Future studies are needed to confirm in larger samples and different populations.

Decreased soluble Nogo-B in serum as a promising biomarker for Parkinson's disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease. It has been reported that circular RNAs (circRNAs) play important roles in several neurological diseases. However, the role and regulatory networks of circRNAs in PD are still largely unclear. In this study, we first compared the global expression level of circRNAs from patients with PD and controls using microarray, then the candidate circRNAs were validated in another PD cohort. The possible functions of these candidate circRNAs were analyzed using Gene Ontology (GO) analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and the regulatory networks of these candidate circRNAs were constructed through circRNA–miRNA–mRNA regulatory networks, protein–protein interaction (PPI) networks, and transcription factor-circRNA networks. The results indicated that hsa_circRNA_101275, hsa_circRNA_103730, and hsa_circRNA_038416 were significantly more highly expressed in patients with PD, while hsa_circRNA_102850 was lower expressed in patients with PD when compared with controls. A circRNA panel combining the four differentially expressed circRNA showed a high diagnostic ability to distinguish patients with PD from controls (AUC = 0.938). Furthermore, GO and KEGG analysis showed these candidate circRNAs were enriched in PI3K–Akt and MAPK signaling pathways. We established circRNA–miRNA–mRNA regulatory networks and identified 10 hub genes (ESR1, PTEN, SHC1, IGF1R, SMAD2, KRAS, MDM2, HIF1A, BMP4, and ACVR2B) were closely related to PD by using PPI network analysis. Besides, these circRNAs were predicted to be regulated through tyrosine hydroxylase (TH)-relevant transcription factors such as GATA2 and GATA3. In conclusion, our results suggest that the circRNA panel and the established circRNA–miRNA–mRNA regulation networks might provide potential novel biomarkers and therapeutic targets for PD.

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The Potential Circular RNAs Biomarker Panel and Regulatory Networks of Parkinson’s Disease

N6‐methyladenosine (m6A), an emerging modification of messenger RNA, has been implicated in many biological processes. However, its role in Parkinson's disease (PD) remains largely unknown. Here, we investigated the role of m6A modification and its underlying mechanism in PD. First, 86 individuals with PD and 86 healthy controls were recruited from a pilot multicenter cohort. Levels of m6A and its modulators in peripheral blood mononuclear cells of patients with PD and controls were measured using an m6A RNA methylation quantification kit and quantitative real‐time PCR. The underlying mechanism of m6A modification in PD was investigated in vitro through RNA immunoprecipitation assay, RNA stability assay, gene silencing or overexpression, western blot, and confocal immunoassay. The results show that mRNA levels of m6A, METTL3, METTL14, and YTHDF2 in patients with PD were significantly lower than in healthy controls, and METTL14 was the main factor involved in abnormal m6A modification. Area under the curve (AUC) analysis suggests METTL14 may provide excellent diagnostic capability for PD, especially when combined with plasma α‐synuclein (α‐syn). Spearman correlation analysis identified that METTL14 was moderately negatively correlated with plasma α‐syn and the motor function of PD. Mechanistic experiments demonstrated that Mettl14 targets and regulates the expression of the α‐syn gene using its methylation function. Overexpression of Mettl14 dramatically increased m6A modification of α‐syn mRNA and weakened its stability. Further results suggest that α‐syn mRNA was modified by Mettl14 binding of an m6A motif in the coding region of α‐syn mRNA, while the reading protein Ythdf2 was involved in recognizing m6A‐modified α‐syn mRNA. Taken together, our results reveal the potential of METTL14 as a novel diagnostic biomarker for PD and identify modification of pathogenic α‐syn protein by METTL14 via an m6A‐YTHDF2‐dependent mechanism.

METTL14 is decreased and regulates m6A modification of α‐synuclein in Parkinson's disease

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and the most common movement disorder. It involves a gradual loss of dopaminergic neurons in the substantia nigra. Although many studies have been conducted, the underlying molecular pathways of PD remain largely unknown. Circular RNAs (circRNAs), a novel class of non-coding RNAs with a covalently closed loop structure, are common in the brain. They are stable, conserved molecules that are widely expressed in eukaryotes in tissue-, cell-, and development-specific patterns. Many circRNAs have recently been identified in nervous system diseases, and some circRNA expression profiles have been linked to PD. Given that recent research has indicated the essential roles of various circRNAs in the development and progression of neurodegenerative diseases, the identification of individual circRNAs may be a promising strategy for finding new treatment targets for PD. Moreover, the search for circRNAs with high specificity and sensitivity will open up new avenues for the early diagnosis and treatment of PD. Herein, we address the biogenesis, properties, and roles of circRNAs and review their potential utility as biomarkers and therapeutic targets in PD.

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Honghu He

Papers

Genome-wide identification of m6A-associated single-nucleotide polymorphisms in Parkinson's disease.

Decreased soluble Nogo-B in serum as a promising biomarker for Parkinson's disease

The Potential Circular RNAs Biomarker Panel and Regulatory Networks of Parkinson’s Disease

METTL14 is decreased and regulates m6A modification of α‐synuclein in Parkinson's disease

The emerging role of circular RNAs in Parkinson’s disease