RNA toxicity and foci formation in microsatellite expansion diseases

Abstract

More than 30 incurable neurological and neuromuscular diseases are caused by simple microsatellite expansions consisted of 3–6 nucleotides. These repeats can occur in non-coding regions and often result in a dominantly inherited disease phenotype that is characteristic of a toxic RNA gain-of-function. The expanded RNA adopts unusual secondary structures, sequesters various RNA binding proteins to form insoluble nuclear foci, and causes cellular defects at a multisystem level. Nuclear foci are dynamic in size, shape and colocalization of RNA binding proteins in different expansion diseases and tissue types. This review sets to provide new insights into the disease mechanisms of RNA toxicity and foci modulation, in light of recent advancement on bi-directional transcription, antisense RNA, repeat-associated non-ATG translation and beyond.

Repeat expansion diseases

“…Large repeats in or near a promoter can profoundly influence expression of the gene as illustrated with FXS above. Repeats within introns can influence alternative splicing of the disease gene, globally perturb splicing by sequestering splicing factors, or perturb transcription (13,148,151). Repeats within the 3’UTR likewise can have a toxic RNA effect by disrupting RNA homeostasis (151).…”

“…Repeats within introns can influence alternative splicing of the disease gene, globally perturb splicing by sequestering splicing factors, or perturb transcription (13,148,151). Repeats within the 3’UTR likewise can have a toxic RNA effect by disrupting RNA homeostasis (151). Finally, repeats within the protein-coding region of the gene are directly translated into protein, leading to altered properties of the encoded disease protein, with deleterious consequences for the nervous system.…”

“…There is a modest inverse correlation of repeat length to age of onset, accounting for approximately one third of the variation in age of onset, and anticipation has been described with paternal transmission (92). The primary disease mechanism is still under investigation but may be a toxic RNA effect (151). …”

Precarious maintenance of simple DNA repeats in eukaryotes

“…Thus, it is not the presence of long microsatellites in the genome per se, but rather rare instances when those microsatellites have expanded within functional genes that they pose a problem to human health. Disease pathology, in turn, often results from an expanded repeat acquiring dominant gain-of-function at the RNA and/or protein levels [6,7]. In addition, long repeat tracts can also lead to the repression of the genes in which they are located, typically by promoting heterochromatin formation [8].…”

Rethinking Unconventional Translation in Neurodegeneration

“…Although these cells can endure even when encountering various stresses, in some neurological diseases they undergo a remarkable molecular reorganization. Repeat expansion disorders are a set of more than 30 genetic diseases, mostly of the nervous system, that are caused by expansion of short repeat sequences of 3–6 nucleotides in a host gene’s coding sequences, introns, or 5′ and 3′ untranslated regions (UTRs) (Zhang and Ashizawa, 2017). During the last two decades, unconventional translation products from various expanded repeat sequences have been repeatedly detected in the nervous system of affected individuals.…”