RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity

Abstract

Although protein-mediated toxicity in neurological disease has been extensively characterized, RNA-mediated toxicity is an emerging mechanism of pathogenesis. In microsatellite expansion disorders, expansion of repeated sequences in noncoding regions gives rise to RNA that produces a toxic gain of function, while expansions in coding regions can disrupt protein function as well as produce toxic RNA. The toxic RNA typically aggregates into nuclear foci and contributes to disease pathogenesis. In many cases, toxicity of the RNA is caused by the disrupted functions of RNA-binding proteins. We will discuss evidence for RNA-mediated toxicity in microsatellite expansion disorders. Different microsatellite expansion disorders are linked with alterations in the same as well as disease-specific RNA-binding proteins. Recent studies have shown that microsatellite expansions can encode multiple repeat-containing toxic RNAs through bidirectional transcription and protein species through repeat-associated non-ATG translation. We will discuss approaches that have characterized the toxic contributions of these various factors.

Figure 1. RNA-binding protein (RBP) function is disrupted in RNAexp-dominant disorders

Microsatellite expansion disorders that produce repeat-containing RNA, or RNAexp, are shown. The relative location within the gene of the repeat expansion is depicted. While other toxic RNAs are generated from the opposite strand in the case of several diseases, only toxic entities known to be related to the disruption fo RBP function are depicted here. The sequence of the RNAexp is drawn for each disorder. This toxic RNA is thought to contribute to pathogenesis through its ability to disrupt one or more RBPs. In some cases, disruption of the downstream function of an RBP has been observed. These mechanisms will be discussed in detail in this review.