Repeat expansion disease: progress and puzzles in disease pathogenesis

Progress in understanding the molecular pathogenesis of repeat expansion diseases has proceeded at a tremendous pace. Here, we review recent developments in the field, including themes and mechanistic pathways that are unexpectedly shared among different repeat expansion diseases.One of the most striking developments has been the discovery that the pathogenesis of some repeat expansion diseases is mediated by toxic RNA species. New insights into the pathogenesis of myotonic dystrophy type 1 and type 2 have revealed that expanded repeats in RNA sequester and deplete the activity of RNA-binding proteins, which leads to widespread defects in splicing. Evidence is discussed suggesting that this mechanism is involved in the pathogenesis of other repeat diseases.Autophagy is a catabolic process in which cell constituents, such as organelles and proteins, are delivered to the lysosomal compartment for degradation. It has recently become evident that autophagy has an important role in some repeat expansion diseases. As autophagy is amenable to pharmacologic manipulation, this has created optimism about the possibility of targeting autophagy for therapeutic benefit. But is autophagy activated or impaired in repeat expansion disease? And should the aim be to activate autophagy or to suppress it? Answers to these questions have evolved as the role of autophagy in disease has been illuminated.Post-translational modifications profoundly influence the toxicity of polyglutamine disease proteins. The characterization of individual post-translational modifications — including phosphorylation, acetylation and sumoylation — has revealed unanticipated insights into polyglutamine disease pathogenesis.The unexpected finding of polyglutamine inclusions in spinocerebellar ataxia type 8 (SCA8) mice and patients with SCA8, a disease caused by the pathological expansion of a CTG trinucleotide repeat, led to the discovery of bidirectional transcription at the SCA8 locus. Therefore it seems that SCA8 pathogenesis might involve two mechanisms: toxic gain-of-function poly-CUG RNA encoded by the sense strand and expression of polyglutamine-expanded peptide encoded by the antisense strand. Could this mechanism apply to other repeat expansion diseases?Microsatellites have been implicated in regulating chromatin organization and utilization. Emerging evidence suggests that pathological repeat expansions may impair this epigenetic regulation.