Key Points
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
The list of developmental and degenerative diseases that are caused by expansion of unstable repeats continues to grow, and is now approaching 20 disorders. The pathogenic mechanisms that underlie these disorders involve either loss of protein function or gain of function at the protein or RNA level. Common themes have emerged within and between these different classes of disease; for example, among disorders that are caused by gain-of-function mechanisms, altered protein conformations are central to pathogenesis, leading to changes in protein activity or abundance. In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.
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Acknowledgements
The authors wish to thank members of the Zoghbi laboratory and Thai Ho (T. Cooper's laboratory) for critical comments. The authors apologize to anyone whose work they did not cite owing to space constraints. The citations are representative works, and are not inclusive of the many important contributing works for a given topic.
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DATABASES
Entrez Gene
OMIM
dentatorubral-pallidoluysian atrophy
Glossary
- POLYRIBOSOME
-
A string of 80S ribosomes that are bound to an mRNA molecule.
- DENDRITIC SPINES
-
Mushroom-shaped structures on neuronal dendrites that receive synaptic input and have postsynaptic densities. Changes in spine shape are thought to be important for modulating synaptic strength.
- LONG-TERM DEPRESSION
-
A long-lasting decrease in synaptic strength to below baseline levels. It is generally induced in the hippocampus by repetitive low-frequency stimulation. It is thought to result from changes in postsynaptic receptor density, although changes in presynaptic release might also have a role.
- GROUP 1 mGluRs
-
Postsynaptic G-protein coupled receptors for the excitatory neurotransmitter glutamate. These receptors have many roles in synaptic plasticity.
- SYNAPTIC PRUNING
-
The selective elimination of weak synapses during brain development.
- SYNAPTIC PLASTICITY
-
The capacity for alterations in synaptic connections between neurons, including changes in the nature, strength or number of interneuronal connections, which subserves learning and memory.
- G QUARTET
-
A secondary structure observed in G-rich RNA in which four consecutive guanosine residues bind to each other to form an intramolecular stem-loop structure.
- RNA-INDUCED SILENCING COMPLEX
-
A multi-protein complex that functions in RNAi pathways to mediate the cleavage of target RNAs.
- ARGONAUTE PROTEINS
-
A family of proteins that are essential for diverse RNA-silencing pathways.
- DICER PROTEINS
-
A highly conserved family of RNaseIII enzymes that mediate dsRNA cleavage. This produces the small RNAs that direct target silencing in RNAi pathways.
- MICRORNA
-
A form of ssRNA typically 20–25 nucleotides long that is thought to regulate the expression of other genes, either through inhibiting protein translation or degrading a target mRNA transcript through a process that is similar to RNA interference.
- CpG ISLANDS
-
Sequences of at least 200 bp that contain both a GC content that is greater than 50% and a high CpG frequency.
- FERRITIN
-
An iron-storage protein.
- ATAXIA
-
The inability to coordinate movement.
- ACONITASE
-
An enzyme that catalyses the reversible hydration of cis-aconitase to yield citrate or isocitrate. Aconitases are involved in the citric acid cycle.
- IRON–SULPHUR (FE–S) CLUSTERS
-
Co-factor-like species that are common in nature and are involved in many cellular processes, such as electron transfer, catalysis, gene regulation and the sensing of iron and oxygen.
- UBIQUITIN–PROTEASOME SYSTEM
-
A key pathway that is involved in the degradation of intracellular proteins, especially of short-lived regulatory proteins. The system uses an enzymatic cascade that involves conjugation of multiple ubiquitin moieties to a protein substrate and degradation of the tagged protein by the 26S proteasome complex.
- PURKINJE CELLS
-
The neurons that convey the output signals of the cerebellar cortex.
- AUTOPHAGY
-
An intracellular pathway that leads to bulk protein degradation and involves the sequestering of cytosol into vesicles for delivery to a degradative organelle.
- AXOPLASM
-
The intracellular fluid of the axon that facilitates vesicle transport.
- CASPASE
-
One of a family of proteases, activated by proteolytic cleavage, that have an important role in apoptosis and inflammation.
- CALPAINS
-
A family of highly conserved and widely expressed cysteine proteases that are activated by a rise in intracellular calcium levels. They have an important role in apoptosis and in modulating intracellular signals in response to stressful conditions.
- SUMOYLATION
-
The post-translational modification of proteins that involves the covalent attachment of small ubiquitin-like modifier (SUMO) and regulates the interactions of those proteins with other macromolecules.
- P/Q-TYPE CALCIUM CHANNEL
-
A high voltage activated calcium channel found in cerebellar Purkinje cells that is responsible for most of the calcium current in these neurons.
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Gatchel, J., Zoghbi, H. Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles. Nat Rev Genet 6, 743–755 (2005). https://doi.org/10.1038/nrg1691
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DOI: https://doi.org/10.1038/nrg1691
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