RNA–protein interactions in unstable microsatellite diseases

Abstract

A novel RNA-mediated disease mechanism has emerged from studies on dominantly inherited neurological disorders caused by unstable microsatellite expansions in non-coding regions of the genome. These non-coding tandem repeat expansions trigger the production of unusual RNAs that gain a toxic function, which involves the formation of RNA repeat structures that interact with, and alter the activities of, various factors required for normal RNA processing as well as additional cellular functions. In this review, we explore the deleterious effects of toxic RNA expression and discuss the various model systems currently available for studying RNA gain-of-function in neurologic diseases. Common themes, including bidirectional transcription and repeat-associated non-ATG (RAN) translation, have recently emerged from expansion disease studies. These and other discoveries have highlighted the need for further investigations designed to provide the additional mechanistic insights essential for future therapeutic development.

MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain

“…RNA-mediated pathogenesis has emerged as an important disease mechanism for a number of neurological and neuromuscular disorders caused by microsatellite expansions (Mohan et al, 2014; Nelson et al, 2013). This unusual pathogenic process has been implicated in diseases in which the expansion mutation originates in a non-coding gene, such as ATXN8 / ATXN8OS , or in the non-coding regions (introns, 5′ UTR, 3′ UTR) of a protein-encoding gene.…”

“…Indeed, the sequestration and activation of RNA processing factors as well as RAN translation have been documented in this disease (Cleary and Ranum, 2014; Echeverria and Cooper, 2012; Mohan et al, 2014). DM types 1 and 2 (DM1, DM2) are progressive and multi-systemic neuromuscular disorders with cardinal manifestations including myotonia, muscle wasting, cardiomyopathy, excessive daytime sleepiness, cerebral atrophy, white matter lesions, cognitive impairments and neurofibrillary tangles (NFTs).…”

Poly(GR) in C9ORF72 -Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons

“…Many proteins bind to G 4 C 2 repeat RNA in cell lysates, and some have been reported to colocalize with RNA foci in patient cells; yet, none of them has been shown to play a key role in disease in a manner like that demonstrated for Muscleblind in myotonic dystrophy (Mohan et al, 2014). On the other hand, in flies and mice, overexpressing noninterrupted, expanded G 4 C 2 repeats in the molecular context of poly(A) + RNA has detrimental effects that are likely due to the production of toxic DPR proteins (Mizielinska et al, 2014; Chew et al, 2015; Freibaum et al, 2015; Tran et al, 2015).…”

Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS

“…Another potential pathogenic mechanism is RNA-mediated toxicity, in which the formation of RNA foci and sequestration of specific RNA-binding proteins is associated with mis-regulation of RNA processing in repeat-expansion diseases (Mohan et al, 2014). In the case of C9ORF72 FTD/ALS, RNA foci are found mostly in the nucleus of multiple cell types, such as brain cells and fibroblasts from patients and neurons derived from induced pluripotent stem cells (iPSCs) (Almeida et al, 2013; DeJesus-Hernandez et al, 2011; Donnelly et al, 2013; Gendron et al, 2013; Lagier-Tourenne et al, 2013; May et al, 2014; Mizielinska et al, 2014; Sareen et al, 2013; Zu et al, 2013).…”