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.

Keywords: Bidirectional transcription; Microsatellite; Neurologic disease; Protein sequestration; RNA foci; RNA-mediated toxicity.

Fig. 1

Neuronal cell model illustrating pathogenic effects of non-coding microsatellite expansions in neurologic disease. Both sense (blue line) and antisense (red line) DNA repeat expansions result in three major downstream deleterious effects (labeled 1–3): (1) protein loss-of-function (LOF) results from hypermethylation of a CG-rich expanded microsatellite repeat in the 5′ UTR and/or promoter region of an affected gene and loss of transcriptional activity (e.g., FXS); (2) RNA gain-of-function (GOF) occurs following bidirectional transcription of expanded repeats and the synthesis of sense (sRNA) and antisense (asRNA), which fold into RNA hairpins (sRNA, blue; asRNA, red) or other stable structures and gain toxic functions either by sequestering an RNA binding protein(s) (RBP) and inhibiting pre-mRNA splicing (2a), pre-mRNA editing (2b), mRNA localization (2c), pri-miR processing (2d) or by triggering aberrant cellular activities such as protein kinase C (PKC) mediated CELF1 hyperphosphorylation (2e); (3) protein GOF due to altered post-translation modifications of other RNA binding proteins (3a) (CELF1 hyperphosphorylation, purple oval with white P in orange star) or RAN translation (3b) (three homopolymeric repeat proteins are shown with one undergoing translation by the ribosome (orange). In addition to these mechanisms, other pathways, including chromatin remodeling, proteome dysregulation and vesicular trafficking, may also contribute to disease pathogenesis, particularly in the CNS (Hernandez-Hernandez et al., 2013).