Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy.

Łukasz J Sznajder,Maurice S Swanson

doi:10.3390/ijms20133365

Łukasz J Sznajder, Maurice S Swanson

Open Access

https://doi.org/10.3390/ijms20133365

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Abstract

Short tandem repeat (STR) or microsatellite, expansions underlie more than 50 hereditary neurological, neuromuscular and other diseases, including myotonic dystrophy types 1 (DM1) and 2 (DM2). Current disease models for DM1 and DM2 propose a common pathomechanism, whereby the transcription of mutant DMPK (DM1) and CNBP (DM2) genes results in the synthesis of CUG and CCUG repeat expansion (CUGexp, CCUGexp) RNAs, respectively. These CUGexp and CCUGexp RNAs are toxic since they promote the assembly of ribonucleoprotein (RNP) complexes or RNA foci, leading to sequestration of Muscleblind-like (MBNL) proteins in the nucleus and global dysregulation of the processing, localization and stability of MBNL target RNAs. STR expansion RNAs also form phase-separated gel-like droplets both in vitro and in transiently transfected cells, implicating RNA-RNA multivalent interactions as drivers of RNA foci formation. Importantly, the nucleation and growth of these nuclear foci and transcript misprocessing are reversible processes and thus amenable to therapeutic intervention. In this review, we provide an overview of potential DM1 and DM2 pathomechanisms, followed by a discussion of MBNL functions in RNA processing and how multivalent interactions between expanded STR RNAs and RNA-binding proteins (RBPs) promote RNA foci assembly.

Highlights

Repetitive DNA sequence elements compose 50–70% of the human genome [1,2]
We focus on two related multisystemic disorders, myotonic dystrophy (DM) type 1 (DM1) and type 2 (DM2), which have served as a paradigm of RNA-mediated diseases
Loss-of-function mechanisms are well documented in Friedreich’s ataxia (FRDA) and a number of folate-sensitive fragile sites, including Fragile XA syndrome (FRAXA) where microsatellite expansions induce epigenetic changes that result in transcriptional repression (Figure 1) [65,66]

Summary

Introduction

Repetitive DNA sequence elements compose 50–70% of the human genome [1,2]. These repetitive sequences include interspersed transposable elements (DNA transposons, RNA retrotransposons) and tandem repeats, including telomeric and centromeric repeats as well as micro-, mini- and mega-, satellites. Microsatellites or short tandem repeats (STRs) composed of 2–10 base pairs (bp), are highly polymorphic in the human population [3] Their propensity to form unusual quadruplex-like, slipped-stranded structures and imperfect hairpins results in an elevated level of DNA replication and repair errors that can lead to STR contractions or expansions [4,5]. Possible STR expansion disease mechanisms include host gene haploinsufficiency, host gene transcript misprocessing [57,58], bidirectional gene transcription [59], repeat-mediated RBP sequestration [60], canonical translation of toxic polyglutamine and polyalanine proteins [61,62] and non-canonical repeat-associated non-AUG (RAN) translation [63]. We evaluate different disease mechanisms for DM1 and DM2 in the context of other microsatellite expansion disorders followed by a more detailed analysis of the pathogenic roles of toxic CUGexp and CCUGexp in RNA processing

Is Myotonic Dystrophy Caused by Haploinsufficiency?

DM1 and DM2 Are RNA-mediated Disorders

B RNA RNA

Emerging Roles for RNA-RNA Multivalent Interactions in DM Disease

Conclusions and Perspectives