Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Diseases of unstable repeat expansion are a diverse group of disorders that are caused by the expansion of trinucleotide, tetranucleotide, or pentanucleotide repeat sequences. The position of the repeat sequence determines whether the pathogenic mechanism leads to loss of protein function, altered or enhanced function, or abnormal RNA–protein interactions. Disorders that are caused by loss-of-function mechanisms include the neurodevelopmental fragile X disorders FRAXA and FRAXE and the degenerative disorder Friedreich ataxia. In these disorders repeat expansion results in transcriptional silencing and loss of the gene product. Understanding the roles of FMRP in FRAXA (translational regulation at the synapse), FMR2 in FRAXE (transcription/signalling), and frataxin in FRDA (mitochondrial protein) is providing an insight into pathogenesis and avenues for therapy. Repeat expansion disorders that are caused by altered protein function — the polyglutamine diseases — include several spinocerebellar ataxias, Huntington disease, spinal and bulbar muscular atrophy, and dentatorubral-pallidoluysian atrophy. These disorders share many points of pathogenic convergence, such as protein misfolding and accumulation, but also unique aspects that are determined by the normal function of the disease protein. Mounting evidence highlights the importance of protein context — the protein sequence in which the polygutamine expansion occurs — as a key determinant of pathogenesis, with modulation of function being driven by the expanded polyglutamine tract. More recently, altered RNA function and/or interactions have been recognized as pathogenic mechanisms in repeat expansion disorders. These alterations underlie dystrophia myotonica 1 and 2 (DM1 and DM2) and fragile X tremor/ataxia syndrome. In DM1 and DM2, the evidence indicates that expanded RNA transcripts lead to the dysregulation of specific RNA-binding proteins; this results in aberrant splicing of several transcripts and a broad, multi-systemic phenotype. In addition to the commonalities within classes of expansion disorders certain similarities also exist between classes. These include importance of normal protein function in protein-mediated disorders, and evidence of protein misfolding in diseases that are caused by both expanded protein and RNA. The convergence of both RNA and protein-mediated diseases on components of the protein quality-control machinery indicates that repeat expansions, whether in the RNA or protein, could elicit a common cellular-response mechanism. Increasing insight into pathogenic mechanisms in these disorders is providing the framework for developing targeted therapies. The late onset of many of the neurodegenerative repeat expansion disorders provides a window of therapeutic opportunity.