Mechanisms of and Solutions for Diseases Caused by Toxic RNA

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 26995

Special Issue Editor


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Guest Editor
University of Siegen, Faculty IV: School of Science and Technology, Institute of Biology / Human Biology, Adolf-Reichwein-Str. 2, 57076 Siegen, Germany
Interests: RNA–protein interaction; neurodegeneration; CAG repeat expansion; translation initiation; splicing

Special Issue Information

Dear Colleagues,

RNA is an important molecule that plays an essential role in both healthy tissue and disease development. Besides coding for proteins, RNA molecules have a diverse range of regulatory functions, including non-coding RNAs that regulate gene expression via RNA interference, ribosomal RNAs, tRNAs, and RNAs that regulate splicing. An RNA’s function depends on the correct three-dimensional structure of the RNA molecule, since interaction partners, such as RNA-binding proteins, recognize specific structural motifs.

Abnormal folding of an RNA, for example due to genetic mutation, can be associated with disease development. For example, expansion mutations of repetitive sequences, such as CAG repeats, lead to an aberrant hairpin structure in the mutant RNA molecule that is not present in the normal RNA. This aberrant hairpin structure can then recruit RNA-binding proteins, which can lead to both the mutant RNA and the RNA-binding proteins having abnormal activity as well as a loss of physiological function of the RNA-binding proteins. In this way, RNA can deregulate a diverse range of cellular pathways and, thus, be toxic. However, the question remains: what are the precise molecular mechanisms underlying RNA-mediated toxicity? Additionally, how can we target toxic RNA species in therapeutic approaches?

These questions are currently under investigation.

The focus of this Special Issue of Toxins will be on molecular mechanisms underlying diseases that are caused by toxic RNA as well as approaches to combating RNA-mediated toxicity.

Prof. Dr. Sybille Krauß
Guest Editor

Manuscript Submission Information

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Keywords

  • RNA
  • three-dimensional structure
  • RNA-mediated toxicity
  • RNA–protein interaction
  • RNA-targeting compounds
  • RNA silencing

Published Papers (3 papers)

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Research

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8 pages, 1539 KiB  
Communication
Aurintricarboxylic Acid Decreases RNA Toxicity in a C. elegans Model of Repeat Expansions
by Maya Braun, Shachar Shoshani, Anna Mellul-Shtern and Yuval Tabach
Toxins 2021, 13(12), 910; https://doi.org/10.3390/toxins13120910 - 20 Dec 2021
Cited by 2 | Viewed by 2978
Abstract
Pathologic expansions of DNA nucleotide tandem repeats may generate toxic RNA that triggers disease phenotypes. RNA toxicity is the hallmark of multiple expansion repeat disorders, including myotonic dystrophy type 1 (DM1). To date, there are no available disease-modifying therapies for DM1. Our aim [...] Read more.
Pathologic expansions of DNA nucleotide tandem repeats may generate toxic RNA that triggers disease phenotypes. RNA toxicity is the hallmark of multiple expansion repeat disorders, including myotonic dystrophy type 1 (DM1). To date, there are no available disease-modifying therapies for DM1. Our aim was to use drug repositioning to ameliorate the phenotype of affected individuals in a nematode model of DM1. As the RNA interference pathway plays a key role in mediating RNA toxicity, we investigated the effect of aurintricarboxylic acid. We demonstrated that by perturbing the RNA interference machinery using aurintricarboxylic acid, we could annihilate the RNA toxicity and ameliorate the phenotype. As our approach targets a universal disease mechanism, it is potentially relevant for more expansion repeat disorders. Full article
(This article belongs to the Special Issue Mechanisms of and Solutions for Diseases Caused by Toxic RNA)
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Review

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26 pages, 2743 KiB  
Review
Infectious RNA: Human Immunodeficiency Virus (HIV) Biology, Therapeutic Intervention, and the Quest for a Vaccine
by Yasemin van Heuvel, Stefanie Schatz, Jamila Franca Rosengarten and Jörn Stitz
Toxins 2022, 14(2), 138; https://doi.org/10.3390/toxins14020138 - 14 Feb 2022
Cited by 10 | Viewed by 18458
Abstract
Different mechanisms mediate the toxicity of RNA. Genomic retroviral mRNA hijacks infected host cell factors to enable virus replication. The viral genomic RNA of the human immunodeficiency virus (HIV) encompasses nine genes encoding in less than 10 kb all proteins needed for replication [...] Read more.
Different mechanisms mediate the toxicity of RNA. Genomic retroviral mRNA hijacks infected host cell factors to enable virus replication. The viral genomic RNA of the human immunodeficiency virus (HIV) encompasses nine genes encoding in less than 10 kb all proteins needed for replication in susceptible host cells. To do so, the genomic RNA undergoes complex alternative splicing to facilitate the synthesis of the structural, accessory, and regulatory proteins. However, HIV strongly relies on the host cell machinery recruiting cellular factors to complete its replication cycle. Antiretroviral therapy (ART) targets different steps in the cycle, preventing disease progression to the acquired immunodeficiency syndrome (AIDS). The comprehension of the host immune system interaction with the virus has fostered the development of a variety of vaccine platforms. Despite encouraging provisional results in vaccine trials, no effective vaccine has been developed, yet. However, novel promising vaccine platforms are currently under investigation. Full article
(This article belongs to the Special Issue Mechanisms of and Solutions for Diseases Caused by Toxic RNA)
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25 pages, 2991 KiB  
Review
Huntingtin and Its Role in Mechanisms of RNA-Mediated Toxicity
by Annika Heinz, Deepti Kailash Nabariya and Sybille Krauss
Toxins 2021, 13(7), 487; https://doi.org/10.3390/toxins13070487 - 14 Jul 2021
Cited by 12 | Viewed by 4856
Abstract
Huntington’s disease (HD) is caused by a CAG-repeat expansion mutation in the Huntingtin (HTT) gene. It is characterized by progressive psychiatric and neurological symptoms in combination with a progressive movement disorder. Despite the ubiquitous expression of HTT, pathological changes occur quite selectively in [...] Read more.
Huntington’s disease (HD) is caused by a CAG-repeat expansion mutation in the Huntingtin (HTT) gene. It is characterized by progressive psychiatric and neurological symptoms in combination with a progressive movement disorder. Despite the ubiquitous expression of HTT, pathological changes occur quite selectively in the central nervous system. Since the discovery of HD more than 150 years ago, a lot of research on molecular mechanisms contributing to neurotoxicity has remained the focal point. While traditionally, the protein encoded by the HTT gene remained the cynosure for researchers and was extensively reviewed elsewhere, several studies in the last few years clearly indicated the contribution of the mutant RNA transcript to cellular dysfunction as well. In this review, we outline recent studies on RNA-mediated molecular mechanisms that are linked to cellular dysfunction in HD models. These mechanisms include mis-splicing, aberrant translation, deregulation of the miRNA machinery, deregulated RNA transport and abnormal regulation of mitochondrial RNA. Furthermore, we summarize recent therapeutical approaches targeting the mutant HTT transcript. While currently available treatments are of a palliative nature only and do not halt the disease progression, recent clinical studies provide hope that these novel RNA-targeting strategies will lead to better therapeutic approaches. Full article
(This article belongs to the Special Issue Mechanisms of and Solutions for Diseases Caused by Toxic RNA)
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