The interplay between epitranscriptomic RNA modifications and neurodegenerative disorders: Mechanistic insights and potential therapeutic strategies

Abstract

Neurodegenerative disorders encompass a group of age-related conditions characterized by the gradual decline in both the structure and functionality of the central nervous system (CNS). RNA modifications, arising from the epitranscriptome or RNA-modifying protein mutations, have recently been observed to contribute significantly to neurodegenerative disorders. Specific modifications like N6-methyladenine (m6A), N1-methyladenine (m1A), 5-methylcytosine (m5C), pseudouridine and adenosine-to-inosine (A-to-I) play key roles, with their regulators serving as crucial therapeutic targets. These epitranscriptomic changes intricately control gene expression, influencing cellular functions and contributing to disease pathology. Dysregulation of RNA metabolism, affecting mRNA processing and noncoding RNA biogenesis, is a central factor in these diseases. This review underscores the complex relationship between RNA modifications and neurodegenerative disorders, emphasizing the influence of RNA modification and the epitranscriptome, exploring the function of RNA modification enzymes in neurodegenerative processes, investigating the functional consequences of RNA modifications within neurodegenerative pathways, and evaluating the potential therapeutic advancements derived from assessing the epitranscriptome.

Keywords: Alzheimer's disease; Parkinson's disease; RNA modifications; epitranscriptomics; neurodegeneration.

Figure 1

Mechanism of RNA modifications in the neurodegeneration and etiology of various neurodegenerative disorders. This shows a schematic pathway from RNA modifications leading to various neurodegenerative disorders. After an RNA gets transcribed, and in case of dysregulated RNA modifications as depicted, brain cells and tissues come under various cellular stresses including oxidative stress, Lewy body formation, neuroinflammation, protein degradation, neuronal cell death, and protein misfolding. These stresses ultimately result in the death of brain cells and tissues, eventually leading to the neurodegeneration and neurodegenerative disorders. NDDs, neurodegenerative disorders. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Role of RNA modifications and related enzymes in regulating gene expression. After RNA is transcribed, “Writers” deposit and install various chemical modifications onto the transcribed RNAs. “Erasers” are the enzymes which remove and eliminate any of the RNA modifications. During the final stage, the modified RNA is translated into a protein by the ribosome. These modifications are recognized and worked upon by the enzymes called “Readers” which then recruit respective machinery during translation. Key enzymes include METTL3/METTL14 (for m6A), NSUN2 (for m5C), TRMT6/61 (for m1A), PUS1 (for Ψ), ADAR (for A‐to‐I), YTHDF1/2/3 (for m6A), HNRNPC (for m6A), FTO (for m6A), and ALKBH5 (for m6A). Different colors represent corresponding RNA modifications. Fat mass and obesity‐associated protein (FTO); m6A, N6‐methyladenine; m5C, 5‐methylcytosine; m1A, N1‐methyladenine; Ψ, pseudouridine; A‐to‐I, adenosine‐to‐inosine. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Regulation of different RNA‐modifying proteins in neurodegenerative disorders. *↑ refers to upregulation and ↓ refers to downregulation of each enzyme. AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; HD, Huntington's disease; PD, Parkinson's disease. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Pathophysiology of PD. PD has been affected by the compromised expression of the various RNA modifications especially m6A, m5C, and A‐to‐I editing. The compromised expression of these specific modifications may induce neurodegeneration by activation of the microglial cells leading to neuroinflammation, protein misfolding that may lead to oxidative stress and Lewy bodies formation, eventually leading to the compromised health of dopaminergic neurons and ultimately leading to the death of these neurons. [Color figure can be viewed at wileyonlinelibrary.com]