Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans

2019 ◽  
Vol 431 (9) ◽  
pp. 1711-1728 ◽  
Author(s):  
Lena Qawasmi ◽  
Maya Braun ◽  
Irene Guberman ◽  
Emiliano Cohen ◽  
Lamis Naddaf ◽  
...  
Keyword(s):  
Disease Phenotype ◽  
Rnai Machinery ◽  
C Elegans ◽  
Cug Repeats

scholarly journals Chromatin Compaction by Small RNAs and the Nuclear RNAi Machinery in C. elegans

2018 ◽  
Author(s):  
Brandon D. Fields ◽  
Scott Kennedy
Keyword(s):  
Small Rnas ◽  
Rna Binding ◽  
Higher Order ◽  
Post Translational Modification ◽  
Rnai Machinery ◽  
Regulate Gene Expression ◽  
Chromatin Compaction ◽  
C Elegans ◽  
Regulation Mechanisms ◽  
Nuclear Rnai

AbstractDNA is organized and compacted into higher-order structures in order to fit within nuclei and to facilitate proper gene regulation. Mechanisms by which higher order chromatin structures are established and maintained are poorly understood. In C. elegans, nuclear-localized small RNAs engage the nuclear RNAi machinery to regulate gene expression and direct the post-translational modification of histone proteins. Here we confirm a recent report suggesting that nuclear small RNAs are required to initiate or maintain chromatin compaction states in C. elegans germ cells. Additionally, we show that experimentally provided small RNAs are sufficient to direct chromatin compaction and that this compaction requires the small RNA-binding Argonaute NRDE-3, the pre-mRNA associated factor NRDE-2, and the HP1-like protein HPL-2. Our results show that small RNAs, acting via the nuclear RNAi machinery and an HP1-like protein, are capable of driving chromatin compaction in C. elegans.

scholarly journals Exogenous misfolded protein oligomers can cross the intestinal barrier and cause a disease phenotype in C. elegans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michele Perni ◽  
Benedetta Mannini ◽  
Catherine K. Xu ◽  
Janet R. Kumita ◽  
Christopher M. Dobson ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
High Throughput Screening ◽  
Intestinal Barrier ◽  
Cytotoxic Agents ◽  
Toxic Effects ◽  
Intestinal Lumen ◽  
Misfolded Protein ◽  
Disease Phenotype ◽  
C Elegans ◽  
Wide Range

AbstractMisfolded protein oligomers are increasingly recognized as highly cytotoxic agents in a wide range of human disorders associated with protein aggregation. In this study, we assessed the possible uptake and resulting toxic effects of model protein oligomers administered to C. elegans through the culture medium. We used an automated machine-vision, high-throughput screening procedure to monitor the phenotypic changes in the worms, in combination with confocal microscopy to monitor the diffusion of the oligomers, and oxidative stress assays to detect their toxic effects. Our results suggest that the oligomers can diffuse from the intestinal lumen to other tissues, resulting in a disease phenotype. We also observed that pre-incubation of the oligomers with a molecular chaperone (αB-crystallin) or a small molecule inhibitor of protein aggregation (squalamine), reduced the oligomer absorption. These results indicate that exogenous misfolded protein oligomers can be taken up by the worms from their environment and spread across tissues, giving rise to pathological effects in regions distant from their place of absorbance.

scholarly journals RNA interference mediates RNA toxicity with parent-of-origin effects in C. elegans expressing CTG repeats

2021 ◽  
Author(s):  
Maya Braun ◽  
Shachar Shoshani ◽  
Joana Teixeira ◽  
Anna Mellul-Shtern ◽  
Maya Miller ◽  
...  
Keyword(s):  
Rna Interference ◽  
Severe Disease ◽  
Epigenetic Inheritance ◽  
Rnai Machinery ◽  
Disease Manifestation ◽  
Ctg Repeats ◽  
Rna Toxicity ◽  
C Elegans ◽  
Repeat Expansions ◽  
Toxic Rna

Nucleotide repeat expansions are a hallmark of over 40 neurodegenerative diseases. These repeats cause RNA toxicity and trigger multisystemic symptoms that worsen with age. RNA toxicity can trigger, through an unclear mechanism, severe disease manifestation in infants that inherited repeats from their mothers. Here we show in Caenorhabditis elegans how RNA interference machinery causes intergenerational toxicity through inheritance of siRNAs derived from CUG repeats. The maternal repeat-derived small RNAs cause transcriptomic changes in the offspring, reduce motility and shorten lifespan. However, the toxicity phenotypes in the offspring can be rescued by perturbing the RNAi machinery in affected mothers. This points to a novel mechanism linking maternal bias and the RNAi machinery and suggests that toxic RNA is transmitted to offspring and causes disease phenotypes through intergenerational epigenetic inheritance.

scholarly journals A cytoplasmic Argonaute protein promotes the inheritance of RNAi

2017 ◽  
Author(s):  
Fei Xu ◽  
Xuezhu Feng ◽  
Xiangyang Chen ◽  
Chenchun Weng ◽  
Qi Yan ◽  
...  
Keyword(s):  
Early Embryogenesis ◽  
Rnai Pathway ◽  
Specific Information ◽  
Argonaute Protein ◽  
Rnai Machinery ◽  
Multiple Generations ◽  
C Elegans ◽  
Mrna Targets ◽  
Germline Genes ◽  
Nuclear Rnai

SummaryRNAi-elicited gene silencing is heritable and can persist for multiple generations after its initial induction in C. elegans. However, the mechanism by which parental-acquired trait-specific information from RNAi is inherited by the progenies is not fully understood. Here, we identified a cytoplasmic Argonaute protein, WAGO-4, necessary for the inheritance of RNAi. WAGO-4 exhibits asymmetrical translocation to the germline during early embryogenesis, accumulates at the perinuclear foci in the germline, and is required for the inheritance of exogenous RNAi targeting both germline- and soma-expressed genes. WAGO-4 binds to 22G-RNAs and their mRNA targets. Interestingly, WAGO-4-associated endogenous 22G-RNAs target the same cohort of germline genes as CSR-1 and contain untemplated addition of uracil at the 3’ ends. The poly(U) polymerase CDE-1 is required for the untemplated uridylation of 22G-RNAs and inheritance of RNAi. Therefore, we conclude that, in addition to the nuclear RNAi pathway, the cytoplasmic RNAi machinery also promotes RNAi inheritance.

scholarly journals Loss of redoxin proteins exacerbates LRRK2‐mediated Parkinson's disease phenotype in C. elegans

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
William Marshall Johnson ◽  
Chen Yao ◽  
Shu Chen ◽  
Amy L. Wilson‐Delfosse ◽  
John J. Mieyal
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Phenotype ◽  
C Elegans

The glycomes of Caenorhabditis elegans and other model organisms

2002 ◽  
Vol 69 ◽  
pp. 117-134 ◽  
Author(s):  
Stuart M. Haslam ◽  
David Gems ◽  
Howard R. Morris ◽  
Anne Dell
Keyword(s):  
Caenorhabditis Elegans ◽  
Current Knowledge ◽  
Structural Data ◽  
Model Organisms ◽  
Entire Genome ◽  
C Elegans ◽  
The Face ◽  
Area Of Concern ◽  
Nematode Worm

There is no doubt that the immense amount of information that is being generated by the initial sequencing and secondary interrogation of various genomes will change the face of glycobiological research. However, a major area of concern is that detailed structural knowledge of the ultimate products of genes that are identified as being involved in glycoconjugate biosynthesis is still limited. This is illustrated clearly by the nematode worm Caenorhabditis elegans, which was the first multicellular organism to have its entire genome sequenced. To date, only limited structural data on the glycosylated molecules of this organism have been reported. Our laboratory is addressing this problem by performing detailed MS structural characterization of the N-linked glycans of C. elegans; high-mannose structures dominate, with only minor amounts of complex-type structures. Novel, highly fucosylated truncated structures are also present which are difucosylated on the proximal N-acetylglucosamine of the chitobiose core as well as containing unusual Fucα1–2Gal1–2Man as peripheral structures. The implications of these results in terms of the identification of ligands for genomically predicted lectins and potential glycosyltransferases are discussed in this chapter. Current knowledge on the glycomes of other model organisms such as Dictyostelium discoideum, Saccharomyces cerevisiae and Drosophila melanogaster is also discussed briefly.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

2020 ◽  
Vol 48 (3) ◽  
pp. 1243-1253 ◽  
Author(s):  
Sukriti Kapoor ◽  
Sachin Kotak
Keyword(s):  
Symmetry Breaking ◽  
Cell Fate ◽  
Cell Cortex ◽  
Axis Formation ◽  
Aurora A Kinase ◽  
Aurora A ◽  
C Elegans ◽  
Cell Embryo ◽  
Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

Behavioural assay for olfactory plasticity in C. elegans

2009 ◽  
Author(s):  
Takaaki Hirotsu ◽  
Yu Hayashi ◽  
Ryo Iwata ◽  
Hirofumi Kunitomo ◽  
Eriko Kage-Nakadai ◽  
...  
Keyword(s):  
C Elegans ◽  
Olfactory Plasticity
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