Disruption of RNA metabolism and its impact on protein homeostasis

Abstract Repeat-associated disorders arise from expansions of nucleotide repeats in coding or non-coding regions, producing RNAs that accumulate and disrupt cellular homeostasis through mechanisms collectively termed RNA repeat toxicity. This process complements proteotoxicity in coding-region expansions and is increasingly recognized as a major contributor to pathogenesis. Expanded repeat RNAs form stable secondary structures that sequester RNA-binding proteins (RBPs), such as Muscleblind-like, alter splicing and activate small RNA pathways, broadly impacting gene expression. Myotonic dystrophy type 1 (DM1) exemplifies RNA-mediated toxicity, with expanded CUG repeats in the DMPK 3′ untranslated region driving nuclear foci formation, RBP sequestration and transcriptome-wide changes. Beyond RNA processing defects, DM1 exhibits systemic dysfunction, notably affecting energy metabolism and mitochondrial function, which recent evidence suggests may be disrupted early and progressively during disease development. These metabolic changes intersect with proteostasis failure, amplifying cellular stress and contributing to systemic pathology. A deeper understanding of the molecular networks that drive metabolic and mitochondrial dysfunction, and their role in proteostasis collapse, will be critical for elucidating disease onset and progression. This knowledge will enable the identification of novel therapeutic targets and biomarkers, offering strategies that go beyond RNA-centric approaches to restore cellular homeostasis in repeat-based disorders. This article is part of the Theo Murphy meeting issue ‘ProteostaSys: a systems view of proteostasis’.