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It is well established that mRNA steady‐state levels do not directly correlate with transcription rate. This is attributed to the multiple post‐transcriptional mechanisms, which control both mRNA turnover and translation within eukaryotic cells. One such mechanism is the removal of the 5' end cap structure of RNAs (decapping). This 5' cap plays a fundamental role in cellular functions related to mRNA processing, transport, translation, quality control, and decay, while its chemical modifications influence the fate of cytoplasmic mRNAs. Decapping is a highly controlled process, performed by multiple decapping enzymes, and regulated by complex cellular networks. In this review, we provide an updated synopsis of 5' end modifications and functions, and give an overview of mRNA decapping enzymes, presenting their enzymatic properties. Focusing on DCP2 decapping enzyme, a major component on the 5'‐3' mRNA decay pathway, we describe cis‐elements and trans‐acting factors that affect its activity, substrate specificity, and cellular localization. Finally, we discuss current knowledge on the biological functions of mRNA decapping and decay factors, highlighting the major questions that remain to be addressed. [ABSTRACT FROM AUTHOR]

Processing bodies (PBs) and stress granules (SGs) are related, cytoplasmic RNA-protein complexes that contribute to post-transcriptional gene regulation in all eukaryotic cells. Both structures contain translationally repressed mRNAs and several proteins involved in silencing, stabilization or degradation of mRNAs, especially under environmental stress. Here, we monitored the dynamic formation of PBs and SGs, in somatic cells of adult worms, using fluorescently tagged protein markers of each complex. Both complexes were accumulated in response to various stress conditions, but distinct modes of SG formation were induced, depending on the insult. We also observed an age-dependent accumulation of PBs but not of SGs. We further showed that direct alterations in PB-related genes can influence aging and normal stress responses, beyond their developmental role. In addition, disruption of SG-related genes had diverse effects on development, fertility, lifespan and stress resistance of worms. Our work therefore underlines the important roles of mRNA metabolism factors in several vital cellular processes and provides insight into their diverse functions in a multicellular organism. [ABSTRACT FROM AUTHOR]

Processing bodies (PBs) and stress granules (SGs) are related, cytoplasmic RNA-protein complexes that contribute to post-transcriptional gene regulation in all eukaryotic cells. Both structures contain translationally repressed mRNAs and several proteins involved in silencing, stabilization or degradation of mRNAs, especially under environmental stress. Here, we monitored the dynamic formation of PBs and SGs, in somatic cells of adult worms, using fluorescently tagged protein markers of each complex. Both complexes were accumulated in response to various stress conditions, but distinct modes of SG formation were induced, depending on the insult. We also observed an age-dependent accumulation of PBs but not of SGs. We further showed that direct alterations in PB-related genes can influence aging and normal stress responses, beyond their developmental role. In addition, disruption of SG-related genes had diverse effects on development, fertility, lifespan and stress resistance of worms. Our work therefore underlines the important roles of mRNA metabolism factors in several vital cellular processes and provides insight into their diverse functions in a multicellular organism. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder representing a major burden on families and society. Some of the main pathological hallmarks of AD are the accumulation of amyloid plaques (Aβ) and tau neurofibrillary tangles. However, it is still unclear how Aβ and tau aggregates promote specific phenotypic outcomes and lead to excessive oxidative DNA damage, neuronal cell death and eventually to loss of memory. Here we utilized a Caenorhabditis elegans (C. elegans) model of human tauopathy to investigate the role of DNA glycosylases in disease development and progression. Transgenic nematodes expressing a pro-aggregate form of tau displayed altered mitochondrial content, decreased lifespan, and cognitive dysfunction. Genetic ablation of either of the two DNA glycosylases found in C. elegans, NTH-1 and UNG-1, improved mitochondrial function, lifespan, and memory impairment. NTH-1 depletion resulted in a dramatic increase of differentially expressed genes, which was not apparent in UNG-1 deficient nematodes. Our findings clearly show that in addition to its enzymatic activity, NTH-1 has non-canonical functions highlighting its modulation as a potential therapeutic intervention to tackle tau-mediated pathology., (Published by Oxford University Press on behalf of Nucleic Acids Research 2024.)

Mitophagy, the selective removal of dysfunctional mitochondria, is pivotal for the maintenance of neuronal function and survival. MEC-12/α-tubulin contributes to neuronal physiology through the regulation of microtubule assembly, intracellular transport and mitochondrial distribution. However, its role in mitochondrial dynamics and mitophagy remains obscure. Here, we demonstrate that MEC-12 influences mitochondrial morphology under basal conditions and regulates the axonal mitochondrial population. Impairment of MEC-12 results in compromised axonal mitophagy under both basal conditions and oxidative stress. Our results uncover the critical role of MEC-12/α-tubulin for maintaining a healthy mitochondrial population in axons and highlight the complex interplay between microtubules, mitophagy and neuronal health., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

Autosomal Dominant Optic Atrophy (ADOA) is a rare neurodegenerative condition, characterized by the bilateral loss of vision due to the degeneration of retinal ganglion cells. Its primary cause is linked to mutations in OPA1 gene, which ultimately affect mitochondrial structure and function. The current lack of successful treatments for ADOA emphasizes the need to investigate the mechanisms driving disease pathogenesis and exploit the potential of animal models for preclinical trials. Among such models, Caenorhabditis elegans stands out as a powerful tool, due its simplicity, its genetic tractability, and its relevance to human biology. Despite the lack of a visual system, the presence of mutated OPA1 in the nematode recapitulates ADOA pathology, by stimulating key pathogenic features of the human condition that can be studied in a fast and relatively non-laborious manner. Here, we provide a detailed guide on how to assess the therapeutic efficacy of chemical compounds, in either small or large scale, by evaluating three crucial phenotypes of humanized ADOA model nematodes, that express pathogenic human OPA1 in their GABAergic motor neurons: axonal mitochondria number, neuronal cell death and defecation cycle time. The described methods can deepen our understanding of ADOA pathogenesis and offer a practical framework for developing novel treatment schemes, providing hope for improved therapeutic outcomes and a better quality of life for individuals affected by this currently incurable condition., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

In response to adverse environmental cues, Caenorhabditis elegans larvae can temporarily arrest development at the second moult and form dauers, a diapause stage that allows for long-term survival. This process is largely regulated by certain evolutionarily conserved signal transduction pathways, but it is also affected by miRNA-mediated post-transcriptional control of gene expression. The 5'-3' mRNA decay mechanism contributes to miRNA-mediated silencing of target mRNAs in many organisms but how it affects developmental decisions during normal or stress conditions is largely unknown. Here, we show that loss of the mRNA decapping complex activity acting in the 5'-3' mRNA decay pathway inhibits dauer formation at the stressful high temperature of 27.5°C, and instead promotes early developmental arrest. Our genetic data suggest that this arrest phenotype correlates with dysregulation of heterochronic gene expression and an aberrant stabilization of lin-14 mRNA at early larval stages. Restoration of neuronal dcap-1 activity was sufficient to rescue growth phenotypes of dcap-1 mutants at both high and normal temperatures, implying the involvement of common developmental timing mechanisms. Our work unveils the crucial role of 5'-3' mRNA degradation in proper regulation of heterochronic gene expression programmes, which proved to be essential for survival under stressful conditions., (© 2017 The Authors.)