Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Repeat expansion disease: progress and puzzles in disease pathogenesis

Key Points

  • 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.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: RNA toxicity in repeat expansion disease.
Figure 2: Sense and antisense toxicity.

Similar content being viewed by others

References

  1. La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

    CAS  PubMed  Google Scholar 

  2. Verkerk, A. J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

    CAS  PubMed  Google Scholar 

  3. Ashley, C. T. et al. Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat. Nature Genet. 4, 244–251 (1993).

    CAS  PubMed  Google Scholar 

  4. Bell, M. V. et al. Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell 64, 861–866 (1991).

    CAS  PubMed  Google Scholar 

  5. Heitz, D. et al. Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science 251, 1236–1239 (1991).

    CAS  PubMed  Google Scholar 

  6. Aslanidis, C. et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature 355, 548–551 (1992).

    CAS  PubMed  Google Scholar 

  7. Brook, J. D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68, 799–808 (1992).

    CAS  PubMed  Google Scholar 

  8. Harley, H. G. et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355, 545–546 (1992).

    CAS  PubMed  Google Scholar 

  9. Jansen, G. et al. Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Nature Genet. 13, 316–324 (1996).

    CAS  PubMed  Google Scholar 

  10. Harris, S., Moncrieff, C. & Johnson, K. Myotonic dystrophy: will the real gene please step forward! Hum. Mol. Genet. 5, 1417–1423 (1996).

    CAS  PubMed  Google Scholar 

  11. Klesert, T. R. et al. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nature Genet. 25, 105–109 (2000).

    CAS  PubMed  Google Scholar 

  12. Sarkar, P. S. et al. Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Nature Genet. 25, 110–114 (2000).

    CAS  PubMed  Google Scholar 

  13. Ranum, L. P., Rasmussen, P. F., Benzow, K. A., Koob, M. D. & Day, J. W. Genetic mapping of a second myotonic dystrophy locus. Nature Genet. 19, 196–198 (1998).

    CAS  PubMed  Google Scholar 

  14. Ricker, K. et al. Proximal myotonic myopathy. Clinical features of a multisystem disorder similar to myotonic dystrophy. Arch. Neurol. 52, 25–31 (1995).

    CAS  PubMed  Google Scholar 

  15. Day, J. W. et al. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology 60, 657–664 (2003).

    CAS  PubMed  Google Scholar 

  16. Liquori, C. L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864–867 (2001).

    CAS  PubMed  Google Scholar 

  17. Timchenko, L. T. Myotonic dystrophy: the role of RNA CUG triplet repeats. Am. J. Hum. Genet. 64, 360–364 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mankodi, A. et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289, 1769–1773 (2000). This paper shows that expression of a CUG repeat expansion in a non-repeat disease RNA is sufficient to produce a myotonic dystrophy-like phenotype in mice. This was an important step in validating the RNA gain-of-function toxicity model.

    CAS  PubMed  Google Scholar 

  19. Philips, A. V., Timchenko, L. T. & Cooper, T. A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737–741 (1998). This study showed a role for altered splicing in the pathogenesis of myotonic dystrophy and also offered an explanation for how the DM1 gene defect could affect a variety of different cell types and tissues.

    CAS  PubMed  Google Scholar 

  20. Kanadia, R. N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003). This work implicated muscleblind in the splicing pathology caused by the CUG repeat expansions in myotonic dystrophy and provided evidence for the genesis and nature of the splicing alterations in this disease.

    CAS  PubMed  Google Scholar 

  21. Miller, J. W. et al. Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Artero, R. et al. The muscleblind gene participates in the organization of Z-bands and epidermal attachments of Drosophila muscles and is regulated by Dmef2. Dev. Biol. 195, 131–143 (1998).

    CAS  PubMed  Google Scholar 

  23. Begemann, G. et al. muscleblind, a gene required for photoreceptor differentiation in Drosophila, encodes novel nuclear Cys3His-type zinc-finger-containing proteins. Development 124, 4321–4331 (1997).

    CAS  PubMed  Google Scholar 

  24. Du, H. et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nature Struct. Mol. Biol.24 Jan 2010 (doi:10.1038/nsmb.1720).

    CAS  Google Scholar 

  25. Hagerman, R. J. et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57, 127–130 (2001).

    CAS  PubMed  Google Scholar 

  26. Jacquemont, S. et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am. J. Hum. Genet. 72, 869–878 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Greco, C. M. et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125, 1760–1771 (2002).

    CAS  PubMed  Google Scholar 

  28. Jin, P. et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39, 739–747 (2003).

    CAS  PubMed  Google Scholar 

  29. Willemsen, R. et al. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum. Mol. Genet. 12, 949–959 (2003).

    CAS  PubMed  Google Scholar 

  30. Jin, P. et al. Pur-α binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron 55, 556–564 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Sofola, O. A. et al. RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55, 565–571 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Katsuno, M. et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35, 843–854 (2002).

    CAS  PubMed  Google Scholar 

  33. Klement, I. A. et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95, 41–53 (1998).

    CAS  PubMed  Google Scholar 

  34. McLeod, C. J., O'Keefe, L. V. & Richards, R. I. The pathogenic agent in Drosophila models of 'polyglutamine' diseases. Hum. Mol. Genet. 14, 1041–1048 (2005).

    CAS  PubMed  Google Scholar 

  35. Li, L. B., Yu, Z., Teng, X. & Bonini, N. M. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453, 1107–1111 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kundu, M. & Thompson, C. B. Autophagy: basic principles and relevance to disease. Annu. Rev. Pathol. 3, 427–455 (2008).

    CAS  PubMed  Google Scholar 

  37. Sapp, E. et al. Huntingtin localization in brains of normal and Huntington's disease patients. Ann. Neurol. 42, 604–612 (1997).

    CAS  PubMed  Google Scholar 

  38. Kegel, K. B. et al. Huntingtin expression stimulates endosomal–lysosomal activity, endosome tubulation, and autophagy. J. Neurosci. 20, 7268–7278 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Petersen, A. et al. Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum. Mol. Genet. 10, 1243–1254 (2001).

    CAS  PubMed  Google Scholar 

  40. Nagata, E., Sawa, A., Ross, C. A. & Snyder, S. H. Autophagosome-like vacuole formation in Huntington's disease lymphoblasts. Neuroreport 15, 1325–1328 (2004).

    PubMed  Google Scholar 

  41. Vig, P. J., Shao, Q., Subramony, S. H., Lopez, M. E. & Safaya, E. Bergmann glial S100B activates myo-inositol monophosphatase 1 and co-localizes to Purkinje cell vacuoles in SCA1 transgenic mice. Cerebellum 8, 231–244 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Zander, C. et al. Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3. Hum. Mol. Genet. 10, 2569–2579 (2001).

    CAS  PubMed  Google Scholar 

  43. Montie, H. L. et al. Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy. Hum. Mol. Genet. 18, 1937–1950 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Yuan, J., Lipinski, M. & Degterev, A. Diversity in the mechanisms of neuronal cell death. Neuron 40, 401–413 (2003).

    CAS  PubMed  Google Scholar 

  45. Yue, Z. et al. A novel protein complex linking the δ2 glutamate receptor and autophagy. Neuron 35, 921–933 (2002).

    CAS  PubMed  Google Scholar 

  46. Nedelsky, N. B., Todd, P. K. & Taylor, J. P. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim. Biophys. Acta 1782, 691–699 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Taylor, J. P. et al. Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum. Mol. Genet. 12, 749–757 (2003).

    CAS  PubMed  Google Scholar 

  48. Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).

    CAS  PubMed  Google Scholar 

  49. Qin, Z. H. et al. Autophagy regulates the processing of amino terminal huntingtin fragments. Hum. Mol. Genet. 12, 3231–3244 (2003).

    CAS  PubMed  Google Scholar 

  50. Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).

    CAS  PubMed  Google Scholar 

  51. Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 859–863 (2007).

    CAS  PubMed  Google Scholar 

  52. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004). This study showed that pharmacological induction of autophagy ameliorated neurodegeneration in animal models of HD.

    CAS  PubMed  Google Scholar 

  53. Pandey, U. B., Batlevi, Y., Baehrecke, E. H. & Taylor, J. P. HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration. Autophagy 3, 643–645 (2007).

    CAS  PubMed  Google Scholar 

  54. Sarkar, S. et al. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum. Mol. Genet. 17, 170–178 (2008).

    CAS  PubMed  Google Scholar 

  55. Tanaka, M. et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nature Med. 10, 148–154 (2004).

    CAS  PubMed  Google Scholar 

  56. Davies, J. E., Sarkar, S. & Rubinsztein, D. C. Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy. Hum. Mol. Genet. 15, 23–31 (2006).

    CAS  PubMed  Google Scholar 

  57. Sarkar, S., Davies, J. E., Huang, Z., Tunnacliffe, A. & Rubinsztein, D. C. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. J. Biol. Chem. 282, 5641–5652 (2007).

    CAS  PubMed  Google Scholar 

  58. Kiffin, R., Bandyopadhyay, U. & Cuervo, A. M. Oxidative stress and autophagy. Antioxid. Redox Signal. 8, 152–162 (2006).

    CAS  PubMed  Google Scholar 

  59. Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248 (2005).

    CAS  PubMed  Google Scholar 

  60. McCray, B. A. & Taylor, J. P. The role of autophagy in age-related neurodegeneration. Neurosignals 16, 75–84 (2008).

    CAS  PubMed  Google Scholar 

  61. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006). This study, and the related study by Hara et al . (reference 62), showed the importance of basal, quality-control autophagy in the CNS. Impairment of basal autophagy was found to cause neurodegeneration with accumulation of ubiquitin-positive inclusions.

    CAS  PubMed  Google Scholar 

  62. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  PubMed  Google Scholar 

  63. Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Komatsu, M. et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl Acad. Sci. USA 104, 14489–14494 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Hollenbeck, P. J. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J. Cell Biol. 121, 305–315 (1993).

    CAS  PubMed  Google Scholar 

  66. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  PubMed  Google Scholar 

  67. Kamaya, H., Hayes, J. J. Jr & Ueda, I. Dissociation constants of local anesthetics and their temperature dependence. Anesth. Analg. 62, 1025–1030 (1983).

    CAS  PubMed  Google Scholar 

  68. Nixon, R. A., Yang, D. S. & Lee, J. H. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4, 590–599 (2008).

    CAS  PubMed  Google Scholar 

  69. Atwal, R. S. et al. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum. Mol. Genet. 16, 2600–2615 (2007).

    CAS  PubMed  Google Scholar 

  70. Li, X. et al. Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity. Mol. Cell. Biol. 29, 6106–6116 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Li, X. et al. Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease. Neurobiol. Dis. 36, 374–383 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. La Spada, A. R. & Taylor, J. P. Polyglutamines placed into context. Neuron 38, 681–684 (2003).

    CAS  PubMed  Google Scholar 

  73. Emamian, E. S. et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38, 375–387 (2003).

    CAS  PubMed  Google Scholar 

  74. Johnson, L. N. & Lewis, R. J. Structural basis for control by phosphorylation. Chem. Rev. 101, 2209–2242 (2001).

    CAS  PubMed  Google Scholar 

  75. Chen, H. K. et al. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113, 457–468 (2003).

    CAS  PubMed  Google Scholar 

  76. Lim, J. et al. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452, 713–718 (2008). This study showed that polyglutamine expansion alters the ratio of ataxin 1 between two alternative protein complexes. This discovery has important implications: it suggests that polyglutamine disease pathogenesis might involve subtle alteration of native protein function rather than an entirely novel gain of function.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Humbert, S. et al. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves huntingtin phosphorylation by Akt. Dev. Cell 2, 831–837 (2002).

    CAS  PubMed  Google Scholar 

  78. Rangone, H. et al. The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur. J. Neurosci. 19, 273–279 (2004).

    PubMed  Google Scholar 

  79. Warby, S. C. et al. Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Hum. Mol. Genet. 14, 1569–1577 (2005).

    CAS  PubMed  Google Scholar 

  80. Pardo, R. et al. Inhibition of calcineurin by FK506 protects against polyglutamine-huntingtin toxicity through an increase of huntingtin phosphorylation at S421. J. Neurosci. 26, 1635–1645 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Difiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat-brain neurons. Neuron 14, 1075–1081 (1995).

    CAS  PubMed  Google Scholar 

  82. Engelender, S. et al. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum. Mol. Genet. 6, 2205–2212 (1997).

    CAS  PubMed  Google Scholar 

  83. Kalchman, M. A. et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nature Genet. 16, 44–53 (1997).

    CAS  PubMed  Google Scholar 

  84. Li, S. H., Gutekunst, C. A., Hersch, S. M. & Li, X. J. Interaction of huntingtin-associated protein with dynactin P150Glued. J. Neurosci. 18, 1261–1269 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, X. J. et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398–402 (1995).

    CAS  PubMed  Google Scholar 

  86. Gauthier, L. R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138 (2004).

    CAS  PubMed  Google Scholar 

  87. Altar, C. A. et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389, 856–860 (1997).

    CAS  PubMed  Google Scholar 

  88. Baquet, Z. C., Gorski, J. A. & Jones, K. R. Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J. Neurosci. 24, 4250–4258 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Zala, D. et al. Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum. Mol. Genet. 17, 3837–3846 (2008).

    CAS  PubMed  Google Scholar 

  90. Colin, E. et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 27, 2124–2134 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Warby, S. C. et al. Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments. Mol. Cell. Neurosci. 40, 121–127 (2009).

    CAS  PubMed  Google Scholar 

  92. Aiken, C. T. et al. Phosphorylation of threonine-3: implications for huntingtin aggregation and neurotoxicity. J. Biol. Chem. 284, 29427–29436 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Schilling, B. et al. Huntingtin phosphorylation sites mapped by mass spectrometry. Modulation of cleavage and toxicity. J. Biol. Chem. 281, 23686–23697 (2006).

    CAS  PubMed  Google Scholar 

  94. Gu, X. et al. Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64, 824–840 (2009).

    Google Scholar 

  95. Thompson, L. M. et al. IKK phosphorylates huntingtin and targets it for degradation by the proteasome and lysosome. J. Cell Biol. 187, 1083–1099 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Fei, E. et al. Phosphorylation of ataxin-3 by glycogen synthase kinase 3β at serine 256 regulates the aggregation of ataxin-3. Biochem. Biophys. Res. Commun. 357, 487–492 (2007).

    CAS  PubMed  Google Scholar 

  97. LaFevre-Bernt, M. A. & Ellerby, L. M. Kennedy's disease. Phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death. J. Biol. Chem. 278, 34918–34924 (2003).

    CAS  PubMed  Google Scholar 

  98. Glozak, M. A., Sengupta, N., Zhang, X. & Seto, E. Acetylation and deacetylation of non-histone proteins. Gene 363, 15–23 (2005).

    CAS  PubMed  Google Scholar 

  99. Mookerjee, S. et al. Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment. J. Neurosci. 29, 15134–15144 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Jeong, J. W. et al. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 111, 709–720 (2002).

    CAS  PubMed  Google Scholar 

  101. Jeong, H. et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137, 60–72 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Steffan, J. S. et al. SUMO modification of huntingtin and Huntington's disease pathology. Science 304, 100–104 (2004).

    CAS  PubMed  Google Scholar 

  103. Subramaniam, S., Sixt, K. M., Barrow, R. & Snyder, S. H. Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324, 1327–1330 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Day, J. W., Schut, L. J., Moseley, M. L., Durand, A. C. & Ranum, L. P. Spinocerebellar ataxia type 8: clinical features in a large family. Neurology 55, 649–657 (2000).

    CAS  PubMed  Google Scholar 

  105. Koob, M. D. et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genet. 21, 379–384 (1999).

    CAS  PubMed  Google Scholar 

  106. Moseley, M. L. et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nature Genet. 38, 758–769 (2006). This paper showed that expansion of the SCA8 triplet repeat is sufficient to produce neurological disease, and demonstrated that transcription of a non-coding RNA on one strand and transcription of a coding CAG RNA on the opposite strand, which gives rise to a polyglutamine protein, both occur at the SCA8 disease locus.

    CAS  PubMed  Google Scholar 

  107. Mutsuddi, M., Marshall, C. M., Benzow, K. A., Koob, M. D. & Rebay, I. The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila. Curr. Biol. 14, 302–308 (2004).

    CAS  PubMed  Google Scholar 

  108. Daughters, R. S. et al. RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet. 5, e1000600 (2009).

    PubMed  PubMed Central  Google Scholar 

  109. Margolis, R. L. et al. A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Ann. Neurol. 50, 373–380 (2001).

    CAS  PubMed  Google Scholar 

  110. Takeshima, H., Komazaki, S., Nishi, M., Iino, M. & Kangawa, K. Junctophilins: a novel family of junctional membrane complex proteins. Mol. Cell 6, 11–22 (2000).

    CAS  PubMed  Google Scholar 

  111. Rudnicki, D. D. et al. Huntington's disease-like 2 is associated with CUG repeat-containing RNA foci. Ann. Neurol. 61, 272–282 (2007).

    CAS  PubMed  Google Scholar 

  112. Nishi, M. et al. Motor discoordination in mutant mice lacking junctophilin type 3. Biochem. Biophys. Res. Commun. 292, 318–324 (2002).

    CAS  PubMed  Google Scholar 

  113. Wang, Y. H., Gellibolian, R., Shimizu, M., Wells, R. D. & Griffith, J. Long CCG triplet repeat blocks exclude nucleosomes: a possible mechanism for the nature of fragile sites in chromosomes. J. Mol. Biol. 263, 511–516 (1996).

    CAS  PubMed  Google Scholar 

  114. Ohlsson, R., Renkawitz, R. & Lobanenkov, V. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 17, 520–527 (2001).

    CAS  PubMed  Google Scholar 

  115. Filippova, G. N. et al. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nature Genet. 28, 335–343 (2001). This study indicated that altered CTCF binding at the DM1 locus could be involved in DM1 pathology. It also implicated CTCF in a trinucleotide repeat disease for the first time, and suggested that CTCF-binding sites are commonly associated with repeat tracts that are susceptible to disease-causing expansion.

    CAS  PubMed  Google Scholar 

  116. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    CAS  PubMed  Google Scholar 

  117. Kim, T. H. et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128, 1231–1245 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Nguyen, P. et al. CTCFL/BORIS is a methylation-independent DNA-binding protein that preferentially binds to the paternal H19 differentially methylated region. Cancer Res. 68, 5546–5551 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Cho, D. H. et al. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol. Cell 20, 483–489 (2005).

    CAS  PubMed  Google Scholar 

  120. Chao, W., Huynh, K. D., Spencer, R. J., Davidow, L. S. & Lee, J. T. CTCF, a candidate trans-acting factor for X-inactivation choice. Science 295, 345–347 (2002).

    CAS  PubMed  Google Scholar 

  121. De Biase, I., Chutake, Y. K., Rindler, P. M. & Bidichandani, S. I. Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription. PLoS ONE 4, e7914 (2009).

    PubMed  PubMed Central  Google Scholar 

  122. Pearson, C. E., Nichol Edamura, K. & Cleary, J. D. Repeat instability: mechanisms of dynamic mutations. Nature Rev. Genet. 6, 729–742 (2005).

    CAS  PubMed  Google Scholar 

  123. Libby, R. T. et al. CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet. 4, e1000257 (2008).

    PubMed  PubMed Central  Google Scholar 

  124. Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. He, Y., Vogelstein, B., Velculescu, V. E., Papadopoulos, N. & Kinzler, K. W. The antisense transcriptomes of human cells. Science 322, 1855–1857 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Preker, P. et al. RNA exosome depletion reveals transcription upstream of active human promoters. Science 322, 1851–1854 (2008).

    CAS  PubMed  Google Scholar 

  127. Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Ladd, P. D. et al. An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum. Mol. Genet. 16, 3174–3187 (2007).

    CAS  PubMed  Google Scholar 

  129. Seong, I. S. et al. Huntingtin facilitates polycomb repressive complex 2. Hum. Mol. Genet. 19, 573–583 (2009).

    PubMed  PubMed Central  Google Scholar 

  130. Kim, M. O. et al. Altered histone monoubiquitylation mediated by mutant huntingtin induces transcriptional dysregulation. J. Neurosci. 28, 3947–3957 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mulders, S. A. et al. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. Proc. Natl Acad. Sci. USA 106, 13915–13920 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Wheeler, T. M. et al. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325, 336–339 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Nedelsky, N. B., Todd, P. K. & Taylor, J. P. Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim. Biophys. Acta 1782, 691–699 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Mukherjee, S., Thomas, M., Dadgar, N., Lieberman, A. P. & Iniguez-Lluhi, J. A. Small ubiquitin-like modifier (SUMO) modification of the androgen receptor attenuates polyglutamine-mediated aggregation. J. Biol. Chem. 284, 21296–21306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Thomas, M. et al. Androgen receptor acetylation site mutations cause trafficking defects, misfolding, and aggregation similar to expanded glutamine tracts. J. Biol. Chem. 279, 8389–8395 (2004).

    CAS  PubMed  Google Scholar 

  136. Palazzolo, I. et al. Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum. Mol. Genet. 16, 1593–1603 (2007).

    CAS  PubMed  Google Scholar 

  137. Terashima, T., Kawai, H., Fujitani, M., Maeda, K. & Yasuda, H. SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines accelerates intranuclear aggregation and cell death. Neuroreport 13, 2359–2364 (2002).

    CAS  PubMed  Google Scholar 

  138. Shen, L. et al. Research on screening and identification of proteins interacting with ataxin-3. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22, 242–247 (2005).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Albert R. La Spada.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

fragile X mental retardation syndrome

myotonic dystrophy type 1

myotonic dystrophy type 2

SCA8

spinal and bulbar muscular atrophy

FURTHER INFORMATION

Albert R. La Spada's homepage

J. Paul Taylor's homepage

Glossary

Post-translational modification

A covalent chemical modification of a protein that takes place after translation.

Haploinsufficiency

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2748

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing