Key Points
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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.
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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.
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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.
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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.
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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?
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Microsatellites have been implicated in regulating chromatin organization and utilization. Emerging evidence suggests that pathological repeat expansions may impair this epigenetic regulation.
Abstract
Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, such as RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade and has shown that the autophagy pathway has an important role in the degradation of misfolded proteins — two themes that are likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalysing new lines of study that should not only elucidate molecular mechanisms of disease but also highlight opportunities for therapeutic intervention for these currently untreatable disorders.
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Acknowledgements
The authors' repeat disease research is supported by the US National Institutes of Health (grants R01 NS041648, R01 GM059356 and R01 EY014061 to A.R.L.S., and grants R01 NS053825 and R01 AG031587 to J.P.T.) and by grants from the Muscular Dystrophy Association to A.R.L.S. and J.P.T.
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DATABASES
OMIM
fragile X mental retardation syndrome
spinal and bulbar muscular atrophy
FURTHER INFORMATION
Glossary
- Post-translational modification
-
A covalent chemical modification of a protein that takes place after translation.
- Haploinsufficiency
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A condition in a diploid organism in which a single functional copy of a gene results in a phenotype, such as a disease.
- Contiguous gene syndrome
-
A multi-symptom disorder caused by the deletion of a large sequence of DNA that encodes several genes.
- Phenocopy
-
A phenotype that is closely similar to a phenotype determined by a different gene.
- Anticipation
-
The tendency of certain diseases to have an earlier age of onset and increasing severity in successive generations.
- Myotonia
-
The failure of muscle to relax immediately after voluntary contraction has stopped.
- Myopathy
-
A disease of the muscle.
- Premutation
-
An unstable mutation that has no phenotypic effect but that is highly likely to mutate to a full mutation during transmission through the germ line, as is seen with some expanding trinucleotide repeats.
- Inclusions
-
Accumulations of proteins and other materials that are visualized as discrete entities at the light microscope level, often after the application of special stains or antibodies.
- Endocytosis
-
The process whereby cells engulf extracellular material through invagination of the plasma membrane to create an endocytic vesicle.
- Neurotrophic factor
-
A small protein that promotes the growth and/or survival of neurons.
- Nucleosome
-
The basic unit of chromatin. A nucleosome contains approximately 146 bp of DNA wrapped around a histone octamer.
- Heterochromatin
-
Parts of chromosomes with an unusual degree of contraction and that consequently have different staining properties from euchromatin at nuclear divisions. Largely composed of repetitive DNA, heterochromatin forms dark bands after Giemsa staining.
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La Spada, A., Taylor, J. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11, 247–258 (2010). https://doi.org/10.1038/nrg2748
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DOI: https://doi.org/10.1038/nrg2748
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