Aurintricarboxylic Acid Decreases RNA Toxicity in a C. elegans Model of Repeat Expansions.

Maya Braun,Anna Mellul-Shtern,Yuval Tabach,Shachar Shoshani

doi:10.3390/toxins13120910

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 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.

Highlights

We revealed the key role of the RNA interference (RNAi) machinery in mediating RNA toxicity in a Caenorhabditis elegans DM1 model [6,7]
We focused on aurintricarboxylic acid (ATA), a triphenyl-methyl molecule that inhibits RNA binding to Argonaute and disrupts the assembly of the RNAinduced silencing complex (RISC) [9]
We searched the literature for disorders, we focused on targeting the RNAi machinery

Summary

Introduction

Toxins 2021, 13, Pathogenic expansions of repeat sequences underlie over 40 neurodegenerative diseases, including myotonic dystrophy type 1 (DM1). 5–37 CTG repeats, while DM1 patients carry more than 50 repeats and may reach several thousand [1]. These expanded repeats trigger RNA toxicity that causes multisystemic symptoms. The RNAs transcribed from the expanded region were shown to disrupt cellular function through gain-of-function- or loss-of-function-type mechanisms. These include sequestration of RNA-binding proteins, such as the alternative splicing regulators MBNL1 and CUGBP1, microRNA and siRNA dysfunction, and RAN translation [2,3,4]. Due to its clinical and genetic variability, DM1 is difficult to treat and there is no disease-modifying therapy currently available [5]

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Conclusion