Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target

Abstract

This review presents detailed information about the structure of triplet repeat RNA and addresses the simple sequence repeats of normal and expanded lengths in the context of the physiological and pathogenic roles played in human cells. First, we discuss the occurrence and frequency of various trinucleotide repeats in transcripts and classify them according to the propensity to form RNA structures of different architectures and stabilities. We show that repeats capable of forming hairpin structures are overrepresented in exons, which implies that they may have important functions. We further describe long triplet repeat RNA as a pathogenic agent by presenting human neurological diseases caused by triplet repeat expansions in which mutant RNA gains a toxic function. Prominent examples of these diseases include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome, which are triggered by mutant CUG and CGG repeats, respectively. In addition, we discuss RNA-mediated pathogenesis in polyglutamine disorders such as Huntington's disease and spinocerebellar ataxia type 3, in which expanded CAG repeats may act as an auxiliary toxic agent. Finally, triplet repeat RNA is presented as a therapeutic target. We describe various concepts and approaches aimed at the selective inhibition of mutant transcript activity in experimental therapies developed for repeat-associated diseases.

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

“…Furthermore, in a Drosophila model of MachadoJoseph disease, another CAG repeat expansion disorder, the MBNL1 protein enhanced CAG repeat RNA toxicity 8,[34][35][36][37][38] . Thus, binding and sequestration of MBNL1 might be one possible mechanism contributing to RNA toxicity in CAG repeat expansion disorders (reviewed in Krzyzosiak et al 40 ). Here we show that expanded CAG repeat stretches in the HTT mRNA bind to the MID1 protein complex and that this protein complex controls this mRNAs' translation.…”

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

“…Long CAG-trinucleotide repeats form RNA stable hairpin structures (10), with the stem portion presenting protein-binding properties (8,11). Abnormal interaction of specific proteins with expanded CAG repeats results in alterations of the normal function of these proteins and consequent perturbations in gene expression and alternative splicing (8,12).…”

Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction

“…In addition to playing critical roles in neuronal development, maintenance, and function, the importance of these regulatory events is further highlighted by the growing number of diseases associated with mutations of certain mRNAs or dysregulation of RBPs or ncRNAs, notably small ncRNAs termed micro-RNAs (miRs), that associate with them (Lukong et al 2008;Cooper et al 2009;Esteller 2011;Im and Kenny 2012). For example, defects affecting the normal expression of mRNAs and/or function of RBPs are central in the etiology and pathogenesis of a broad spectrum of neuronal diseases, including the neurodegenerative disorders fragile X syndrome, fragile X tremor ataxia syndrome 1 (Li and Jin 2012), spinal muscular atrophy (SMA) (Fallini et al 2012b), Huntington's disease (Krzyzosiak et al 2012), and amyotrophic lateral sclerosis (ALS) (Fiesel and Kahle 2011;Strong and Volkening 2011).…”