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Deregulation of RNA Metabolism in Microsatellite Expansion Diseases

  • Chaitali Misra
  • Feikai Lin
  • Auinash Kalsotra
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 20)

Abstract

RNA metabolism impacts different steps of mRNA life cycle including splicing, polyadenylation, nucleo-cytoplasmic export, translation, and decay. Growing evidence indicates that defects in any of these steps lead to devastating diseases in humans. This chapter reviews the various RNA metabolic mechanisms that are disrupted in Myotonic Dystrophy—a trinucleotide repeat expansion disease—due to dysregulation of RNA-Binding Proteins. We also compare Myotonic Dystrophy to other microsatellite expansion disorders and describe how some of these mechanisms commonly exert direct versus indirect effects toward disease pathologies.

Keywords

Microsatellite repeat expansions Post-transcriptional gene regulation RNA toxicity Alternative splicing and polyadenylation RNA-binding proteins 

Notes

Acknowledgments

A.K. is supported by grants from the US National Institute of Health (R01HL126845), Muscular Dystrophy Association (MDA514335), and the Center for Advanced Study at the University of Illinois. C.M. is supported by the American Heart Association post-doctoral fellowship (16POST29950018).

References

  1. 1.
    Arif W, Datar G, Kalsotra A. Intersections of post-transcriptional gene regulatory mechanisms with intermediary metabolism. Biochim Biophys Acta. 2017;1860(3):349–62.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Lewis CJ, Pan T, Kalsotra A. RNA modifications and structures cooperate to guide RNA-protein interactions. Nat Rev Mol Cell Biol. 2017;18(3):202–10.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet. 2016;17(1):19–32.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Brinegar AE, Cooper TA. Roles for RNA-binding proteins in development and disease. Brain Res. 2016;1647:1–8.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Mirkin SM. Expandable DNA repeats and human disease. Nature. 2007;447(7147):932–40.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    La Spada AR, Taylor JP. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet. 2010;11(4):247–58.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Renoux AJ, Todd PK. Neurodegeneration the RNA way. Prog Neurobiol. 2012;97(2):173–89.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    O’Rourke JR, Swanson MS. Mechanisms of RNA-mediated disease. J Biol Chem. 2009;284(12):7419–23.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Zhang N, Ashizawa T. RNA toxicity and foci formation in microsatellite expansion diseases. Curr Opin Genet Dev. 2017;44:17–29.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Jain A, Vale RD. RNA phase transitions in repeat expansion disorders. Nature. 2017;546(7657):243–7.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Heitz D, Rousseau F, Devys D, Saccone S, Abderrahim H, Le Paslier D, Cohen D, Vincent A, Toniolo D, Della Valle G, et al. Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science. 1991;251(4998):1236–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science. 1991;252(5013):1711–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Oberle I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer A, Boue J, Bertheas MF, Mandel JL. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991;252(5009):1097–102.PubMedCrossRefGoogle Scholar
  14. 14.
    Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, 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. 1991;65(5):905–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Bhakar AL, Dolen G, Bear MF. The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci. 2012;35:417–43.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Santoro MR, Bray SM, Warren ST. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol. 2012;7:219–45.PubMedCrossRefGoogle Scholar
  17. 17.
    Ashley CT Jr, Wilkinson KD, Reines D, Warren ST. FMR1 protein: conserved RNP family domains and selective RNA binding. Science. 1993;262(5133):563–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Brown V, Small K, Lakkis L, Feng Y, Gunter C, Wilkinson KD, Warren ST. Purified recombinant Fmrp exhibits selective RNA binding as an intrinsic property of the fragile X mental retardation protein. J Biol Chem. 1998;273(25):15521–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Siomi H, Choi M, Siomi MC, Nussbaum RL, Dreyfuss G. Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome. Cell. 1994;77(1):33–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell. 1993;74(2):291–8.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352(6330):77–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci. 2007;30:575–621.PubMedCrossRefGoogle Scholar
  23. 23.
    Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997;90(3):537–48.PubMedCrossRefGoogle Scholar
  24. 24.
    DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;277(5334):1990–3.PubMedCrossRefGoogle Scholar
  25. 25.
    Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997;19(2):333–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Li LB, Bonini NM. Roles of trinucleotide-repeat RNA in neurological disease and degeneration. Trends Neurosci. 2010;33(6):292–8.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 2005;6(10):743–55.PubMedCrossRefGoogle Scholar
  28. 28.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–56.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257–68.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW III, Rademakers R, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013;77(4):639–46.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339(6125):1335–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS, et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A. 2013;110(19):7778–83.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 2013;110(51):E4968–77.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes Dev. 2003;17(4):419–37.PubMedCrossRefGoogle Scholar
  35. 35.
    Wheeler TM. Myotonic dystrophy: therapeutic strategies for the future. Neurotherapeutics. 2008;5(4):592–600.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Harper P. Myotonic dystrophy. London: W.B. Saunders; 2001.Google Scholar
  37. 37.
    Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T, 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. 1992;68(4):799–808.PubMedCrossRefGoogle Scholar
  38. 38.
    Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O’Hoy K, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science. 1992;255(5049):1253–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LP. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293(5531):864–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Yum K, Wang ET, Kalsotra A. Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes. Curr Opin Genet Dev. 2017;44:30–7.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Groh WJ, Groh MR, Saha C, Kincaid JC, Simmons Z, Ciafaloni E, Pourmand R, Otten RF, Bhakta D, Nair GV, et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med. 2008;358(25):2688–97.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Heatwole C, Bode R, Johnson N, Quinn C, Martens W, McDermott MP, Rothrock N, Thornton C, Vickrey B, Victorson D, et al. Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology. 2012;79(4):348–57.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Phillips MF, Harper PS. Cardiac disease in myotonic dystrophy. Cardiovasc Res. 1997;33(1):13–22.PubMedCrossRefGoogle Scholar
  44. 44.
    Salehi LB, Bonifazi E, Stasio ED, Gennarelli M, Botta A, Vallo L, Iraci R, Massa R, Antonini G, Angelini C, et al. Risk prediction for clinical phenotype in myotonic dystrophy type 1: data from 2,650 patients. Genet Test. 2007;11(1):84–90.PubMedCrossRefGoogle Scholar
  45. 45.
    Jansen G, Groenen PJ, Bachner D, Jap PH, Coerwinkel M, Oerlemans F, van den Broek W, Gohlsch B, Pette D, Plomp JJ, et al. Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Nat Genet. 1996;13(3):316–24.PubMedCrossRefGoogle Scholar
  46. 46.
    Berul CI, Maguire CT, Aronovitz MJ, Greenwood J, Miller C, Gehrmann J, Housman D, Mendelsohn ME, Reddy S. DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. J Clin Invest. 1999;103(4):R1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Thornton CA, Wymer JP, Simmons Z, McClain C, Moxley RT III. Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nat Genet. 1997;16(4):407–9.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Klesert TR, Cho DH, Clark JI, Maylie J, Adelman J, Snider L, Yuen EC, Soriano P, Tapscott SJ. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat Genet. 2000;25(1):105–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, Krym M, Thornton CA. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science. 2000;289(5485):1769–73.PubMedCrossRefGoogle Scholar
  50. 50.
    Gomes-Pereira M, Cooper TA, Gourdon G. Myotonic dystrophy mouse models: towards rational therapy development. Trends Mol Med. 2011;17(9):506–17.PubMedCrossRefGoogle Scholar
  51. 51.
    Echeverria GV, Cooper TA. RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res. 2012;1462:100–11.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Cleary JD, Ranum LP. Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Curr Opin Genet Dev. 2014;26:6–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Mohan A, Goodwin M, Swanson MS. RNA-protein interactions in unstable microsatellite diseases. Brain Res. 2014;1584:3–14.PubMedCrossRefGoogle Scholar
  54. 54.
    Chau A, Kalsotra A. Developmental insights into the pathology of and therapeutic strategies for DM1: back to the basics. Dev Dyn. 2015;244(3):377–90.PubMedCrossRefGoogle Scholar
  55. 55.
    Nilsen TW, Graveley BR. Expansion of the eukaryotic proteome by alternative splicing. Nature. 2010;463(7280):457–63.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Kalsotra A, Cooper TA. Functional consequences of developmentally regulated alternative splicing. Nat Rev Genet. 2011;12(10):715–29.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Begemann G, Paricio N, Artero R, Kiss I, Perez-Alonso M, Mlodzik M. muscleblind, a gene required for photoreceptor differentiation in Drosophila, encodes novel nuclear Cys3His-type zinc-finger-containing proteins. Development. 1997;124(21):4321–31.PubMedGoogle Scholar
  58. 58.
    Ho TH, Charlet BN, Poulos MG, Singh G, Swanson MS, Cooper TA. Muscleblind proteins regulate alternative splicing. EMBO J. 2004;23(15):3103–12.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kanadia RN, Urbinati CR, Crusselle VJ, Luo D, Lee YJ, Harrison JK, Oh SP, Swanson MS. Developmental expression of mouse muscleblind genes Mbnl1, Mbnl2 and Mbnl3. Gene Expr Patterns. 2003;3(4):459–62.PubMedCrossRefGoogle Scholar
  60. 60.
    Konieczny P, Stepniak-Konieczna E, Sobczak K. MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res. 2014;42(17):10873–87.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Kalsotra A, Xiao X, Ward AJ, Castle JC, Johnson JM, Burge CB, Cooper TA. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci U S A. 2008;105(51):20333–8.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Wang ET, Cody NA, Jog S, Biancolella M, Wang TT, Treacy DJ, Luo S, Schroth GP, Housman DE, Reddy S, et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell. 2012;150(4):710–24.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Du H, Cline MS, Osborne RJ, Tuttle DL, Clark TA, Donohue JP, Hall MP, Shiue L, Swanson MS, Thornton CA, et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol. 2010;17(2):187–93.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Adereth Y, Dammai V, Kose N, Li R, Hsu T. RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1. Nat Cell Biol. 2005;7(12):1240–7.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Masuda A, Andersen HS, Doktor TK, Okamoto T, Ito M, Andresen BS, Ohno K. CUGBP1 and MBNL1 preferentially bind to 3′ UTRs and facilitate mRNA decay. Sci Rep. 2012;2:209.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Osborne RJ, Lin X, Welle S, Sobczak K, O’Rourke JR, Swanson MS, Thornton CA. Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy. Hum Mol Genet. 2009;18(8):1471–81.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Rau F, Freyermuth F, Fugier C, Villemin JP, Fischer MC, Jost B, Dembele D, Gourdon G, Nicole A, Duboc D, et al. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol. 2011;18(7):840–5.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thornton CA, Esson D, Timmers AM, Hauswirth WW, Swanson MS. A muscleblind knockout model for myotonic dystrophy. Science. 2003;302(5652):1978–80.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Kino Y, Mori D, Oma Y, Takeshita Y, Sasagawa N, Ishiura S. Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. Hum Mol Genet. 2004;13(5):495–507.PubMedCrossRefGoogle Scholar
  70. 70.
    Warf MB, Berglund JA. MBNL binds similar RNA structures in the CUG repeats of myotonic dystrophy and its pre-mRNA substrate cardiac troponin T. RNA. 2007;13(12):2238–51.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Yuan Y, Compton SA, Sobczak K, Stenberg MG, Thornton CA, Griffith JD, Swanson MS. Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs. Nucleic Acids Res. 2007;35(16):5474–86.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Fardaei M, Rogers MT, Thorpe HM, Larkin K, Hamshere MG, Harper PS, Brook JD. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum Mol Genet. 2002;11(7):805–14.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet. 2004;13(24):3079–88.PubMedCrossRefGoogle Scholar
  74. 74.
    Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 2000;19(17):4439–48.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Batra R, Charizanis K, Manchanda M, Mohan A, Li M, Finn DJ, Goodwin M, Zhang C, Sobczak K, Thornton CA, et al. Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. Mol Cell. 2014;56(2):311–22.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C, Yuan Y, Shiue L, Cline M, Scotti MM, Xia G, et al. Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron. 2012;75(3):437–50.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Poulos MG, Batra R, Li M, Yuan Y, Zhang C, Darnell RB, Swanson MS. Progressive impairment of muscle regeneration in muscleblind-like 3 isoform knockout mice. Hum Mol Genet. 2013;22(17):3547–58.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Lee KY, Li M, Manchanda M, Batra R, Charizanis K, Mohan A, Warren SA, Chamberlain CM, Finn D, Hong H, et al. Compound loss of muscleblind-like function in myotonic dystrophy. EMBO Mol Med. 2013;5(12):1887–900.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Suenaga K, Lee KY, Nakamori M, Tatsumi Y, Takahashi MP, Fujimura H, Jinnai K, Yoshikawa H, Du H, Ares M Jr, et al. Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. PLoS One. 2012;7(3):e33218.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Goodwin M, Mohan A, Batra R, Lee KY, Charizanis K, Fernandez Gomez FJ, Eddarkaoui S, Sergeant N, Buee L, Kimura T, et al. MBNL sequestration by toxic RNAs and RNA misprocessing in the myotonic dystrophy brain. Cell Rep. 2015;12(7):1159–68.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Sergeant N, Sablonniere B, Schraen-Maschke S, Ghestem A, Maurage CA, Wattez A, Vermersch P, Delacourte A. Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet. 2001;10(19):2143–55.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Ladd AN, Charlet N, Cooper TA. The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol Cell Biol. 2001;21(4):1285–96.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Fardaei M, Larkin K, Brook JD, Hamshere MG. In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts. Nucleic Acids Res. 2001;29(13):2766–71.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Kuyumcu-Martinez NM, Wang GS, Cooper TA. Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell. 2007;28(1):68–78.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Kalsotra A, Wang K, Li PF, Cooper TA. MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development. Genes Dev. 2010;24(7):653–8.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Kalsotra A, Singh RK, Gurha P, Ward AJ, Creighton CJ, Cooper TA. The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue, dramatically altering miRNA and mRNA expression. Cell Rep. 2014;6(2):336–45.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Lin X, Miller JW, Mankodi A, Kanadia RN, Yuan Y, Moxley RT, Swanson MS, Thornton CA. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet. 2006;15(13):2087–97.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Pelletier R, Hamel F, Beaulieu D, Patry L, Haineault C, Tarnopolsky M, Schoser B, Puymirat J. Absence of a differentiation defect in muscle satellite cells from DM2 patients. Neurobiol Dis. 2009;36(1):181–90.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Salisbury E, Schoser B, Schneider-Gold C, Wang GL, Huichalaf C, Jin B, Sirito M, Sarkar P, Krahe R, Timchenko NA, et al. Expression of RNA CCUG repeats dysregulates translation and degradation of proteins in myotonic dystrophy 2 patients. Am J Pathol. 2009;175(2):748–62.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001;29(1):40–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Charlet BN, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002;10(1):45–53.CrossRefGoogle Scholar
  92. 92.
    Wang ET, Ward AJ, Cherone JM, Giudice J, Wang TT, Treacy DJ, Lambert NJ, Freese P, Saxena T, Cooper TA, et al. Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins. Genome Res. 2015;25(6):858–71.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Kim DH, Langlois MA, Lee KB, Riggs AD, Puymirat J, Rossi JJ. HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Nucleic Acids Res. 2005;33(12):3866–74.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Paul S, Dansithong W, Kim D, Rossi J, Webster NJ, Comai L, Reddy S. Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing. EMBO J. 2006;25(18):4271–83.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Paul S, Dansithong W, Jog SP, Holt I, Mittal S, Brook JD, Morris GE, Comai L, Reddy S. Expanded CUG repeats dysregulate RNA splicing by altering the stoichiometry of the muscleblind 1 complex. J Biol Chem. 2011;286(44):38427–38.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Krzyzosiak WJ, Sobczak K, Wojciechowska M, Fiszer A, Mykowska A, Kozlowski P. Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target. Nucleic Acids Res. 2012;40(1):11–26.PubMedCrossRefGoogle Scholar
  97. 97.
    Laurent FX, Sureau A, Klein AF, Trouslard F, Gasnier E, Furling D, Marie J. New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic Acids Res. 2012;40(7):3159–71.PubMedCrossRefGoogle Scholar
  98. 98.
    Holt I, Mittal S, Furling D, Butler-Browne GS, Brook JD, Morris GE. Defective mRNA in myotonic dystrophy accumulates at the periphery of nuclear splicing speckles. Genes Cells. 2007;12(9):1035–48.PubMedCrossRefGoogle Scholar
  99. 99.
    Smith KP, Byron M, Johnson C, Xing Y, Lawrence JB. Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains. J Cell Biol. 2007;178(6):951–64.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Taliaferro JM, Vidaki M, Oliveira R, Olson S, Zhan L, Saxena T, Wang ET, Graveley BR, Gertler FB, Swanson MS, et al. Distal alternative last exons localize mRNAs to neural projections. Mol Cell. 2016;61(6):821–33.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Wang ET, Taliaferro JM, Lee JA, Sudhakaran IP, Rossoll W, Gross C, Moss KR, Bassell GJ. Dysregulation of mRNA localization and translation in genetic disease. J Neurosci. 2016;36(45):11418–26.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Vlasova IA, Tahoe NM, Fan D, Larsson O, Rattenbacher B, Sternjohn JR, Vasdewani J, Karypis G, Reilly CS, Bitterman PB, et al. Conserved GU-rich elements mediate mRNA decay by binding to CUG-binding protein 1. Mol Cell. 2008;29(2):263–70.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Lee JE, Lee JY, Wilusz J, Tian B, Wilusz CJ. Systematic analysis of cis-elements in unstable mRNAs demonstrates that CUGBP1 is a key regulator of mRNA decay in muscle cells. PLoS One. 2010;5(6):e11201.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Moraes KC, Wilusz CJ, Wilusz J. CUG-BP binds to RNA substrates and recruits PARN deadenylase. RNA. 2006;12(6):1084–91.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Timchenko L. Molecular mechanisms of muscle atrophy in myotonic dystrophies. Int J Biochem Cell Biol. 2013;45(10):2280–7.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Dasgupta T, Ladd AN. The importance of CELF control: molecular and biological roles of the CUG-BP, Elav-like family of RNA-binding proteins. Wiley Interdiscip Rev RNA. 2012;3(1):104–21.PubMedCrossRefGoogle Scholar
  107. 107.
    Rattenbacher B, Beisang D, Wiesner DL, Jeschke JC, von Hohenberg M, St Louis-Vlasova IA, Bohjanen PR. Analysis of CUGBP1 targets identifies GU-repeat sequences that mediate rapid mRNA decay. Mol Cell Biol. 2010;30(16):3970–80.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Zhang L, Lee JE, Wilusz J, Wilusz CJ. The RNA-binding protein CUGBP1 regulates stability of tumor necrosis factor mRNA in muscle cells: implications for myotonic dystrophy. J Biol Chem. 2008;283(33):22457–63.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Russo J, Lee JE, Lopez CM, Anderson J, Nguyen TP, Heck AM, Wilusz J, Wilusz CJ. The CELF1 RNA-binding protein regulates decay of signal recognition particle mRNAs and limits secretion in mouse myoblasts. PLoS One. 2017;12(1):e0170680.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Vlasova-St Louis I, Dickson AM, Bohjanen PR, Wilusz CJ. CELFish ways to modulate mRNA decay. Biochim Biophys Acta. 2013;1829(6–7):695–707.PubMedCrossRefGoogle Scholar
  111. 111.
    Timchenko NA, Iakova P, Cai ZJ, Smith JR, Timchenko LT. Molecular basis for impaired muscle differentiation in myotonic dystrophy. Mol Cell Biol. 2001;21(20):6927–38.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Timchenko NA, Patel R, Iakova P, Cai ZJ, Quan L, Timchenko LT. Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis. J Biol Chem. 2004;279(13):13129–39.PubMedCrossRefGoogle Scholar
  113. 113.
    Salisbury E, Sakai K, Schoser B, Huichalaf C, Schneider-Gold C, Nguyen H, Wang GL, Albrecht JH, Timchenko LT. Ectopic expression of cyclin D3 corrects differentiation of DM1 myoblasts through activation of RNA CUG-binding protein, CUGBP1. Exp Cell Res. 2008;314(11–12):2266–78.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Gambardella S, Rinaldi F, Lepore SM, Viola A, Loro E, Angelini C, Vergani L, Novelli G, Botta A. Overexpression of microRNA-206 in the skeletal muscle from myotonic dystrophy type 1 patients. J Transl Med. 2010;8:48.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Perbellini R, Greco S, Sarra-Ferraris G, Cardani R, Capogrossi MC, Meola G, Martelli F. Dysregulation and cellular mislocalization of specific miRNAs in myotonic dystrophy type 1. Neuromuscul Disord. 2011;21(2):81–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Fernandez-Costa JM, Garcia-Lopez A, Zuniga S, Fernandez-Pedrosa V, Felipo-Benavent A, Mata M, Jaka O, Aiastui A, Hernandez-Torres F, Aguado B, et al. Expanded CTG repeats trigger miRNA alterations in Drosophila that are conserved in myotonic dystrophy type 1 patients. Hum Mol Genet. 2013;22(4):704–16.PubMedCrossRefGoogle Scholar
  117. 117.
    Greco S, Perfetti A, Fasanaro P, Cardani R, Capogrossi MC, Meola G, Martelli F. Deregulated microRNAs in myotonic dystrophy type 2. PLoS One. 2012;7(6):e39732.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Perfetti A, Greco S, Bugiardini E, Cardani R, Gaia P, Gaetano C, Meola G, Martelli F. Plasma microRNAs as biomarkers for myotonic dystrophy type 1. Neuromuscul Disord. 2014;24(6):509–15.PubMedCrossRefGoogle Scholar
  119. 119.
    Fernandez-Torron R, Garcia-Puga M, Emparanza JI, Maneiro M, Cobo AM, Poza JJ, Espinal JB, Zulaica M, Ruiz I, Martorell L, et al. Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation. Neurology. 2016;87(12):1250–7.PubMedCrossRefGoogle Scholar
  120. 120.
    Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011;108(1):260–5.PubMedCrossRefGoogle Scholar
  121. 121.
    Cleary JD, Ranum LP. Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet. 2013;22(R1):R45–51.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Zu T, Cleary JD, Liu Y, Banez-Coronel M, Bubenik JL, Ayhan F, Ashizawa T, Xia G, Clark HB, Yachnis AT, et al. RAN translation regulated by Muscleblind proteins in myotonic dystrophy type 2. Neuron. 2017;95(6):1292–1305 e1295.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Kearse MG, Todd PK. Repeat-associated non-AUG translation and its impact in neurodegenerative disease. Neurotherapeutics. 2014;11(4):721–31.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Green KM, Linsalata AE, Todd PK. RAN translation-what makes it run? Brain Res. 2016;1647:30–42.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Todd PK, Oh SY, Krans A, He F, Sellier C, Frazer M, Renoux AJ, Chen KC, Scaglione KM, Basrur V, et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron. 2013;78(3):440–55.PubMedCrossRefGoogle Scholar
  126. 126.
    Banez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, Pletnikova O, Borchelt DR, Ross CA, Margolis RL, et al. RAN translation in Huntington disease. Neuron. 2015;88(4):667–77.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Harrison AF, Shorter J. RNA-binding proteins with prion-like domains in health and disease. Biochem J. 2017;474(8):1417–38.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, et al. Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a Drosophila model of C9ORF72 FTD/ALS. Neuron. 2015;87(6):1207–14.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Liu EY, Cali CP, Lee EB. RNA metabolism in neurodegenerative disease. Dis Models Mech. 2017;10(5):509–18.CrossRefGoogle Scholar
  130. 130.
    Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416–38.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 2001;20(7):1774–84.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Ling JP, Pletnikova O, Troncoso JC, Wong PC. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science. 2015;349(6248):650–5.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Shiga A, Ishihara T, Miyashita A, Kuwabara M, Kato T, Watanabe N, Yamahira A, Kondo C, Yokoseki A, Takahashi M, et al. Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS. PLoS One. 2012;7(8):e43120.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, Konig J, Hortobagyi T, Nishimura AL, Zupunski V, et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci. 2011;14(4):452–8.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Costessi L, Porro F, Iaconcig A, Muro AF. TDP-43 regulates beta-adducin (Add2) transcript stability. RNA Biol. 2014;11(10):1280–90.PubMedCrossRefGoogle Scholar
  136. 136.
    Liu X, Li D, Zhang W, Guo M, Zhan Q. Long non-coding RNA gadd7 interacts with TDP-43 and regulates Cdk6 mRNA decay. EMBO J. 2012;31(23):4415–27.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci. 2007;35(2):320–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SSW, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A, et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron. 2014;81(3):536–43.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Yang L, Embree LJ, Tsai S, Hickstein DD. Oncoprotein TLS interacts with serine-arginine proteins involved in RNA splicing. J Biol Chem. 1998;273(43):27761–4.PubMedCrossRefGoogle Scholar
  140. 140.
    Wang X, Arai S, Song X, Reichart D, Du K, Pascual G, Tempst P, Rosenfeld MG, Glass CK, Kurokawa R. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature. 2008;454(7200):126–30.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Couthouis J, Hart MP, Shorter J, DeJesus-Hernandez M, Erion R, Oristano R, Liu AX, Ramos D, Jethava N, Hosangadi D, et al. A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci U S A. 2011;108(52):20881–90.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Ticozzi N, Vance C, Leclerc AL, Keagle P, Glass JD, McKenna-Yasek D, Sapp PC, Silani V, Bosco DA, Shaw CE, et al. Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis. Am J Med Genet B Neuropsychiatric Genet. 2011;156B(3):285–90.CrossRefGoogle Scholar
  143. 143.
    Neumann M, Bentmann E, Dormann D, Jawaid A, DeJesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, et al. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain. 2011;134(Pt 9):2595–609.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Couthouis J, Hart MP, Erion R, King OD, Diaz Z, Nakaya T, Ibrahim F, Kim HJ, Mojsilovic-Petrovic J, Panossian S, et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet. 2012;21(13):2899–911.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466(7310):1069–75.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495(7442):467–73.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, Pliner HA, Abramzon Y, Marangi G, Winborn BJ, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014;17(5):664–6.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Murray DT, Kato M, Lin Y, Thurber KR, Hung I, McKnight SL, Tycko R. Structure of FUS protein fibrils and its relevance to self-assembly and phase separation of low-complexity domains. Cell. 2017;171(3):615–627 e616.PubMedCrossRefGoogle Scholar
  149. 149.
    Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron. 2015;88(4):678–90.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539(7628):197–206.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015;525(7567):129–33.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW III, Sun S, Herdy JR, Bieri G, et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015;18(9):1226–9.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56–61.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, Tatzelt J, Mann M, Winklhofer KF, Hartl FU, et al. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science. 2016;351(6269):173–6.PubMedCrossRefGoogle Scholar
  155. 155.
    Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, Cika J, Coughlin M, Messing J, Molliex A, et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell. 2016;167(3):774–788 e717.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Lin Y, Mori E, Kato M, Xiang S, Wu L, Kwon I, McKnight SL. Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell. 2016;167(3):789–802 e712.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Shi KY, Mori E, Nizami ZF, Lin Y, Kato M, Xiang S, Wu LC, Ding M, Yu Y, Gall JG, et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc Natl Acad Sci U S A. 2017;114(7):E1111–7.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Hagerman RJ, Hull CE, Safanda JF, Carpenter I, Staley LW, O’Connor RA, Seydel C, Mazzocco MM, Snow K, Thibodeau SN, et al. High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. Am J Med Genet. 1994;51(4):298–308.PubMedCrossRefGoogle Scholar
  159. 159.
    Coffey SM, Cook K, Tartaglia N, Tassone F, Nguyen DV, Pan R, Bronsky HE, Yuhas J, Borodyanskaya M, Grigsby J, et al. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A. 2008;146A(8):1009–16.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Jacquemont S, Hagerman RJ, Leehey M, Grigsby J, Zhang L, Brunberg JA, Greco C, Des Portes V, Jardini T, Levine R, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet. 2003;72(4):869–78.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Greco CM, Hagerman RJ, Tassone F, Chudley AE, Del Bigio MR, Jacquemont S, Leehey M, Hagerman PJ. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain. 2002;125(Pt 8):1760–71.PubMedCrossRefGoogle Scholar
  162. 162.
    Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. J Investig Med. 2009;57(8):830–6.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Penagarikano O, Mulle JG, Warren ST. The pathophysiology of fragile x syndrome. Annu Rev Genomics Hum Genet. 2007;8:109–29.PubMedCrossRefGoogle Scholar
  164. 164.
    Sreeram N, Wren C, Bhate M, Robertson P, Hunter S. Cardiac abnormalities in the fragile X syndrome. Br Heart J. 1989;61(3):289–91.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Lozano R, Azarang A, Wilaisakditipakorn T, Hagerman RJ. Fragile X syndrome: a review of clinical management. Intractable Rare Dis Res. 2016;5(3):145–57.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Holmes SE, O’Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, Kwak NG, Ingersoll-Ashworth RG, Sherr M, Sumner AJ, et al. Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat Genet. 1999;23(4):391–2.PubMedCrossRefGoogle Scholar
  167. 167.
    O’Hearn E, Holmes SE, Calvert PC, Ross CA, Margolis RL. SCA-12: tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology. 2001;56(3):299–303.PubMedCrossRefGoogle Scholar
  168. 168.
    Ranum LP, Rasmussen PF, Benzow KA, Koob MD, Day JW. Genetic mapping of a second myotonic dystrophy locus. Nat Genet. 1998;19(2):196–8.PubMedCrossRefGoogle Scholar
  169. 169.
    Peric S, Rakocevic Stojanovic V, Mandic Stojmenovic G, Ilic V, Kovacevic M, Parojcic A, Pesovic J, Mijajlovic M, Savic-Pavicevic D, Meola G. Clusters of cognitive impairment among different phenotypes of myotonic dystrophy type 1 and type 2. Neurol Sci. 2017;38(3):415–23.PubMedCrossRefGoogle Scholar
  170. 170.
    Tieleman AA, Knoop H, van de Logt AE, Bleijenberg G, van Engelen BG, Overeem S. Poor sleep quality and fatigue but no excessive daytime sleepiness in myotonic dystrophy type 2. J Neurol Neurosurg Psychiatry. 2010;81(9):963–7.PubMedCrossRefGoogle Scholar
  171. 171.
    Hund E, Jansen O, Koch MC, Ricker K, Fogel W, Niedermaier N, Otto M, Kuhn E, Meinck HM. Proximal myotonic myopathy with MRI white matter abnormalities of the brain. Neurology. 1997;48(1):33–7.PubMedCrossRefGoogle Scholar
  172. 172.
    Schneider-Gold C, Bellenberg B, Prehn C, Krogias C, Schneider R, Klein J, Gold R, Lukas C. Cortical and subcortical grey and white matter atrophy in myotonic dystrophies Type 1 and 2 is associated with cognitive impairment, depression and daytime sleepiness. PLoS One. 2015;10(6):e0130352.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Meola G, Sansone V, Perani D, Scarone S, Cappa S, Dragoni C, Cattaneo E, Cotelli M, Gobbo C, Fazio F, et al. Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2). Neuromuscul Disord. 2003;13(10):813–21.PubMedCrossRefGoogle Scholar
  174. 174.
    Meola G, Cardani R. Myotonic dystrophy type 2: an update on clinical aspects, genetic and pathomolecular mechanism. J Neuromuscul Dis. 2015;2(s2):S59–71.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Giordana MT, Ferrero P, Grifoni S, Pellerino A, Naldi A, Montuschi A. Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review. Neurol Sci. 2011;32(1):9–16.PubMedCrossRefGoogle Scholar
  176. 176.
    Graff-Radford NR, Woodruff BK. Frontotemporal dementia. Semin Neurol. 2007;27(1):48–57.PubMedCrossRefGoogle Scholar
  177. 177.
    Kirshner HS. Frontotemporal dementia and primary progressive aphasia, a review. Neuropsychiatr Dis Treat. 2014;10:1045–55.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Thomas PS Jr, Fraley GS, Damian V, Woodke LB, Zapata F, Sopher BL, Plymate SR, La Spada AR. Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. Hum Mol Genet. 2006;15(14):2225–38.PubMedCrossRefGoogle Scholar
  179. 179.
    The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72(6):971–83.CrossRefGoogle Scholar
  180. 180.
    Louis ED, Lee P, Quinn L, Marder K. Dystonia in Huntington’s disease: prevalence and clinical characteristics. Mov Disord. 1999;14(1):95–101.PubMedCrossRefGoogle Scholar
  181. 181.
    Kim SD, Fung VS. An update on Huntington’s disease: from the gene to the clinic. Curr Opin Neurol. 2014;27(4):477–83.PubMedCrossRefGoogle Scholar
  182. 182.
    Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994;6(1):9–13.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet. 1994;6(1):14–8.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Ikeuchi T, Koide R, Tanaka H, Onodera O, Igarashi S, Takahashi H, Kondo R, Ishikawa A, Tomoda A, Miike T, et al. Dentatorubral-pallidoluysian atrophy: clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat. Ann Neurol. 1995;37(6):769–75.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Nucifora FC Jr, Ellerby LM, Wellington CL, Wood JD, Herring WJ, Sawa A, Hayden MR, Dawson VL, Dawson TM, Ross CA. Nuclear localization of a non-caspase truncation product of atrophin-1, with an expanded polyglutamine repeat, increases cellular toxicity. J Biol Chem. 2003;278(15):13047–55.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. 1998;95(1):41–53.PubMedCrossRefGoogle Scholar
  187. 187.
    Skinner PJ, Vierra-Green CA, Emamian E, Zoghbi HY, Orr HT. Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic mice. NeuroMolecular Med. 2002;1(1):33–42.PubMedCrossRefGoogle Scholar
  188. 188.
    Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996;14(3):277–84.PubMedCrossRefGoogle Scholar
  189. 189.
    Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14(3):269–76.PubMedCrossRefGoogle Scholar
  190. 190.
    Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 1996;14(3):285–91.PubMedCrossRefGoogle Scholar
  191. 191.
    Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8(3):221–8.PubMedCrossRefGoogle Scholar
  192. 192.
    Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997;15(1):62–9.PubMedCrossRefGoogle Scholar
  193. 193.
    David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, Saudou F, Antoniou E, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet. 1997;17(1):65–70.PubMedCrossRefGoogle Scholar
  194. 194.
    Koide R, Kobayashi S, Shimohata T, Ikeuchi T, Maruyama M, Saito M, Yamada M, Takahashi H, Tsuji S. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet. 1999;8(11):2047–53.PubMedCrossRefGoogle Scholar
  195. 195.
    Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, Rommens JM, Uyama E, Nohira O, et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet. 1998;18(2):164–7.PubMedCrossRefGoogle Scholar
  196. 196.
    Anvar SY, Raz Y, Verway N, van der Sluijs B, Venema A, Goeman JJ, Vissing J, van der Maarel SM, t Hoen PA, van Engelen BG, et al. A decline in PABPN1 induces progressive muscle weakness in oculopharyngeal muscle dystrophy and in muscle aging. Aging. 2013;5(6):412–26.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Stromme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lutcherath V, Gedeon AK, Wallace RH, Scheffer IE, et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet. 2002;30(4):441–5.PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Ropers HH, Hamel BC. X-linked mental retardation. Nat Rev Genet. 2005;6(1):46–57.PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Nawara M, Szczaluba K, Poirier K, Chrzanowska K, Pilch J, Bal J, Chelly J, Mazurczak T. The ARX mutations: a frequent cause of X-linked mental retardation. Am J Med Genet A. 2006;140(7):727–32.PubMedCrossRefPubMedCentralGoogle Scholar
  200. 200.
    Messaed C, Rouleau GA. Molecular mechanisms underlying polyalanine diseases. Neurobiol Dis. 2009;34(3):397–405.PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Winblad S, Lindberg C, Hansen S. Cognitive deficits and CTG repeat expansion size in classical myotonic dystrophy type 1 (DM1). Behav Brain Funct. 2006;2:16.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LP. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999;21(4):379–84.PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Ikeda Y, Dalton JC, Moseley ML, Gardner KL, Bird TD, Ashizawa T, Seltzer WK, Pandolfo M, Milunsky A, Potter NT, et al. Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia. Am J Hum Genet. 2004;75(1):3–16.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Paulson HL. The spinocerebellar ataxias. J Neuroophthalmol. 2009;29(3):227–37.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Jin P, Duan R, Qurashi A, Qin Y, Tian D, Rosser TC, Liu H, Feng Y, Warren ST. Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron. 2007;55(4):556–64.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Sofola OA, Jin P, Qin Y, Duan R, Liu H, de Haro M, Nelson DL, Botas J. RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron. 2007;55(4):565–71.PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Timchenko LT, Miller JW, Timchenko NA, DeVore DR, Datar KV, Lin L, Roberts R, Caskey CT, Swanson MS. Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic Acids Res. 1996;24(22):4407–14.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Sellier C, Rau F, Liu Y, Tassone F, Hukema RK, Gattoni R, Schneider A, Richard S, Willemsen R, Elliott DJ, et al. Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. EMBO J. 2010;29(7):1248–61.PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991;66(4):817–22.PubMedCrossRefPubMedCentralGoogle Scholar
  210. 210.
    Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM, Fragile X. mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci. 1997;17(5):1539–47.PubMedCrossRefGoogle Scholar
  211. 211.
    Khandjian EW, Huot ME, Tremblay S, Davidovic L, Mazroui R, Bardoni B. Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles. Proc Natl Acad Sci U S A. 2004;101(36):13357–62.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Stefani G, Fraser CE, Darnell JC, Darnell RB. Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci. 2004;24(33):7272–6.PubMedCrossRefGoogle Scholar
  213. 213.
    Greenough WT, Klintsova AY, Irwin SA, Galvez R, Bates KE, Weiler IJ. Synaptic regulation of protein synthesis and the fragile X protein. Proc Natl Acad Sci U S A. 2001;98(13):7101–6.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Hokkanen S, Feldmann HM, Ding H, Jung CK, Bojarski L, Renner-Muller I, Schuller U, Kretzschmar H, Wolf E, Herms J. Lack of Pur-alpha alters postnatal brain development and causes megalencephaly. Hum Mol Genet. 2012;21(3):473–84.PubMedCrossRefGoogle Scholar
  215. 215.
    Qurashi A, Li W, Zhou JY, Peng J, Jin P. Nuclear accumulation of stress response mRNAs contributes to the neurodegeneration caused by Fragile X premutation rCGG repeats. PLoS Genet. 2011;7(6):e1002102.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Li Y, Jin P. RNA-mediated neurodegeneration in fragile X-associated tremor/ataxia syndrome. Brain Res. 2012;1462:112–7.PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Wang GS, Kearney DL, De Biasi M, Taffet G, Cooper TA. Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J Clin Invest. 2007;117(10):2802–11.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Ho TH, Savkur RS, Poulos MG, Mancini MA, Swanson MS, Cooper TA. Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy. J Cell Sci. 2005;118(Pt 13):2923–33.PubMedCrossRefGoogle Scholar
  219. 219.
    Ladd AN, Stenberg MG, Swanson MS, Cooper TA. Dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Dev Dyn. 2005;233(3):783–93.PubMedCrossRefGoogle Scholar
  220. 220.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–3.PubMedCrossRefGoogle Scholar
  221. 221.
    Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602–11.PubMedCrossRefGoogle Scholar
  222. 222.
    Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8.PubMedCrossRefGoogle Scholar
  223. 223.
    Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–11.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, Annu K, Baker M, Perkerson RB, Kurti A, et al. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron. 2017;95(4):808–16. e809PubMedCrossRefPubMedCentralGoogle Scholar
  225. 225.
    Todd PK. Making sense of the antisense transcripts in C9FTD/ALS. Acta Neuropathol. 2013;126(6):785–7.PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C, et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci. 2011;14(4):459–68.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Ito D, Suzuki N. Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology. 2011;77(17):1636–43.PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Ito D, Seki M, Tsunoda Y, Uchiyama H, Suzuki N. Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann Neurol. 2011;69(1):152–62.PubMedCrossRefGoogle Scholar
  229. 229.
    Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 2010;29(16):2841–57.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    King OD, Gitler AD, Shorter J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 2012;1462:61–80.PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell. 2012;149(4):753–67.PubMedCrossRefGoogle Scholar
  232. 232.
    Lim L, Wei Y, Lu Y, Song J. ALS-causing mutations significantly perturb the self-assembly and interaction with nucleic acid of the intrinsically disordered prion-like domain of TDP-43. PLoS Biol. 2016;14(1):e1002338.PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell. 2015;163(1):123–33.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, Swanson MS, Ranum LP. RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet. 2009;5(8):e1000600.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Mutsuddi M, Marshall CM, Benzow KA, Koob MD, Rebay I. The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila. Curr Biol. 2004;14(4):302–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of IllinoisUrbana-ChampaignUSA
  2. 2.Carl R. Woese Institute of Genomic BiologyUniversity of IllinoisUrbana-ChampaignUSA

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