Deregulation of RNA Metabolism in Microsatellite Expansion Diseases

Abstract

RNA metabolism impacts different steps of mRNA life cycle including splicing, polyadenylation, nucleo-cytoplasmic export, translation, and decay. Growing evidence indicates that defects in any of these steps lead to devastating diseases in humans. This chapter reviews the various RNA metabolic mechanisms that are disrupted in Myotonic Dystrophy-a trinucleotide repeat expansion disease-due to dysregulation of RNA-Binding Proteins. We also compare Myotonic Dystrophy to other microsatellite expansion disorders and describe how some of these mechanisms commonly exert direct versus indirect effects toward disease pathologies.

An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I

“…Alternative splicing events are generally induced by cis-acting regulatory elements within pre-mRNAs that promote or inhibit exon recognition, as well as by the expression or activity of trans-acting factors such as MBNL and CELF proteins. MBNLs and CELFs bind to these cis elements and regulate the accessibility of the spliceosome to splice sites [ 53 , 72 ]. As represented in Figure 4 , mutant DMPK mRNAs are spliced and polyadenylated but their nuclear sequestration, due to the CUG repeats in the 3′UTR, prevents translation [ 73 ].…”

Synthetic small-molecule RNA ligands: future prospects as therapeutic agents

“…Expanded RNA repeats have been identified as the cause of various diseases and have then been exploited as potential targets of small-molecule RNA ligands for potential therapeutic applications. 53 To date, over 25 human genes with tandem repeat expansions have been identified. These diseasecausing repeats can be located in 5′ and 3′ untranslated regions (UTRs) such as in fragile X-associated tremor ataxia syndrome (FXTAS) and myotonic dystrophy type 1 (DM1), in introns such as in spinocerebellar ataxia type 10 (SCA10) and myotonic dystrophy type 2 (DM2) or in coding regions such as in Huntington's disease (HD).…”

Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies

“…While RNA repeats may be invariably toxic to multiple cell types, several studies have highlighted the selective vulnerability of neurons to RNA repeats, which likely underlies cognitive, behavioral, and motor symptoms in neurological MRE disorders (Wenzel et al 2010;Ariza et al 2015;Bavassano et al 2017;Jimenez-Sanchez et al 2017;Selvaraj et al 2018). Indeed, while somatic mosaicism and genetic anticipation account for differences in the precise number of repeating sequence units present in any given patient cell, the selective neuronal vulnerability to MREs is hypothesized to emerge from neurons' highly complex morphologies with unique activity-dependent and developmental requirements for spatiotemporally restricted changes in gene expression (McMurray 2010; Roselli and Caroni 2015;Fu et al 2018;Misra et al 2018;Nussbacher et al 2019). Disruptions to homeostatic controls of neuronal gene expression in response to age, stress, pathological repeat length, or environmental changes may underlie the aberrant executive and cognitive dysfunction present in patients with MRE disorders.…”

“…Pathological MRE within multiple genes expressed in neurons can yield diverse pathological consequences that are clinically distinct for each disorder and may affect unique neuronal populations. Nearly all MRE disorders have been linked to transcription of the MRE, as opposed to pathological perturbation of genomic or chromatin landscapes, but hypermethylation and transcriptional silencing of the FMR1 locus in Fragile X syndrome (FXS) presents an interesting exception associated with neurodevelopmental conditions, such as autism and intellectual disability ( Shin et al 2009 ; Todd and Paulson 2010 ; Hagerman et al 2017 ; Rohilla and Gagnon 2017 ; Misra et al 2018 ; Swinnen et al 2020 ). Indeed, expanded CGG repeat tracts in FMR1 RNA may hybridize to its genomic locus forming RNA:DNA duplexes that promote epigenetic silencing through polycomb group complexes around week 11 of human gestation ( Colak et al 2014 ; Kumari and Usdin 2014 ).…”

“…Indeed, while somatic mosaicism and genetic anticipation account for differences in the precise number of repeating sequence units present in any given patient cell, the selective neuronal vulnerability to MREs is hypothesized to emerge from neurons’ highly complex morphologies with unique activity-dependent and developmental requirements for spatiotemporally restricted changes in gene expression ( McMurray 2010 ; Roselli and Caroni 2015 ; Fu et al 2018 ; Misra et al 2018 ; Nussbacher et al 2019 ). Disruptions to homeostatic controls of neuronal gene expression in response to age, stress, pathological repeat length, or environmental changes may underlie the aberrant executive and cognitive dysfunction present in patients with MRE disorders.…”