RNA Related Pathology in Huntington’s Disease

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)

Abstract

This chapter summarises research investigating the expression of huntingtin sense and anti-sense transcripts, the effect of the mutation on huntingtin processing as well as the more global effect of the mutation on the coding and non-coding transcriptomes. The huntingtin gene is ubiquitously expressed, although expression levels vary between tissues and cell types. A SNP that affects NF-ĸB binding in the huntingtin promoter modulates the expression level of huntingtin transcripts and is associated with the age of disease onset. Incomplete splicing between exon 1 and exon 2 has been shown to result in the expression of a small polyadenylated mRNA that encodes the highly pathogenic exon 1 huntingtin protein. This occurs in a CAG-repeat length dependent manner in all full-length mouse models of HD as well as HD patient post-mortem brains and fibroblasts. An antisense transcript to huntingtin is generated that contains a CUG repeat that is expanded in HD patients. In myotonic dystrophy, expanded CUG repeats form RNA foci in cell nuclei that bind specific proteins (e.g. MBL1). Short, pure CAG RNAs of approximately 21 nucleotides that have been processed by DICER can inhibit the translation of other CAG repeat containing mRNAs. The HD mutation affects the transcriptome at the level of mRNA expression, splicing and the expression of non-coding RNAs. Finally, expanded repetitive stretched of nucleotides can lead to RAN translation, in which the ribosome translates from the expanded repeat in all possible reading frames, producing proteins with various poly-amino acid tracts. The extent to which these events contribute to HD pathogenesis is largely unknown.

Keywords

Huntingtin transcripts Antisense RNA Non-coding RNA Huntingtin splicing RAN translation 

References

  1. 1.
    Huntington G (2003) On chorea. George Huntington, M.D. J Neuropsychiatry Clinical Neurosciences 15(1):109–112CrossRefGoogle Scholar
  2. 2.
    Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY et al (1983) A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306(5940):234–238CrossRefGoogle Scholar
  3. 3.
    The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Huntington’s Dis Collaborative Res Group. Cell 72(6):971–983CrossRefGoogle Scholar
  4. 4.
    Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6(12):919–930CrossRefPubMedGoogle Scholar
  5. 5.
    DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277(5334):1990–1993CrossRefGoogle Scholar
  6. 6.
    Schilling G, Klevytska A, Tebbenkamp AT, Juenemann K, Cooper J, Gonzales V, Slunt H, Poirer M, Ross CA, Borchelt DR (2007) Characterization of huntingtin pathologic fragments in human Huntington disease, transgenic mice, and cell models. J Neuropathol Exp Neurol 66(4):313–320CrossRefGoogle Scholar
  7. 7.
    Lunkes A, Lindenberg KS, Ben-Haiem L, Weber C, Devys D, Landwehrmeyer GB, Mandel JL, Trottier Y (2002) Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol Cell 10(2):259–269CrossRefGoogle Scholar
  8. 8.
    Ratovitski T, Gucek M, Jiang H, Chighladze E, Waldron E, D’Ambola J, Hou Z, Liang Y, Poirier MA, Hirschhorn RR, Graham R, Hayden MR, Cole RN, Ross CA (2009) Mutant huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells. J Biol Chem 284(16):10855–10867CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ratovitski T, Nakamura M, D’Ambola J, Chighladze E, Liang Y, Wang W, Graham R, Hayden MR, Borchelt DR, Hirschhorn RR, Ross CA (2007) N-terminal proteolysis of full-length mutant huntingtin in an inducible PC12 cell model of Huntington’s disease. Cell Cycle 6(23):2970–2981CrossRefPubMedGoogle Scholar
  10. 10.
    Landles C, Sathasivam K, Weiss A, Woodman B, Moffitt H, Finkbeiner S, Sun B, Gafni J, Ellerby LM, Trottier Y, Richards WG, Osmand A, Paganetti P, Bates GP (2010) Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease. J Biol Chem 285(12):8808–8823CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Barbaro BA, Lukacsovich T, Agrawal N, Burke J, Bornemann DJ, Purcell JM, Worthge SA, Caricasole A, Weiss A, Song W, Morozova OA, Colby DW, Marsh JL (2015) Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington’s disease. Hum Mol Genet 24(4):913–925CrossRefPubMedGoogle Scholar
  12. 12.
    Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F (2015) Proteomics. Tissue-based map of the human proteome. Science 347(6220):1260419CrossRefGoogle Scholar
  13. 13.
    Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3):493–506CrossRefGoogle Scholar
  14. 14.
    Ng CW, Yildirim F, Yap YS, Dalin S, Matthews BJ, Velez PJ, Labadorf A, Housman DE, Fraenkel E (2013) Extensive changes in DNA methylation are associated with expression of mutant huntingtin. Proc Natl Acad Sci U S A 110(6):2354–2359CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Holzmann C, Schmidt T, Thiel G, Epplen JT, Riess O (2001) Functional characterization of the human Huntington’s disease gene promoter. Brain Res Mol Brain Res 92(1–2):85–97CrossRefGoogle Scholar
  16. 16.
    Coles R, Caswell R, Rubinsztein DC (1998) Functional analysis of the Huntington’s disease (HD) gene promoter. Hum Mol Genet 7(5):791–800CrossRefGoogle Scholar
  17. 17.
    Becanovic K, Norremolle A, Neal SJ, Kay C, Collins JA, Arenillas D, Lilja T, Gaudenzi G, Manoharan S, Doty CN, Beck J, Lahiri N, Portales-Casamar E, Warby SC, Connolly C, De Souza RA, Network RIotEHsD, Tabrizi SJ, Hermanson O, Langbehn DR, Hayden MR, Wasserman WW, Leavitt BR (2015) A SNP in the HTT promoter alters NF-kappaB binding and is a bidirectional genetic modifier of Huntington disease. Nat Neurosci 18(6):807–816CrossRefGoogle Scholar
  18. 18.
    Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ, Tabrizi SJ (2015) Huntington disease. Nat Rev Dis Primers 1:15005CrossRefPubMedGoogle Scholar
  19. 19.
    Duan R, Sharma S, Xia Q, Garber K, Jin P (2014) Towards understanding RNA-mediated neurological disorders. J Genet Genomics = Yi chuan xue bao 41(9):473–484CrossRefPubMedGoogle Scholar
  20. 20.
    Groh M, Gromak N (2014) Out of balance: R-loops in human disease. PLoS Genet 10(9):e1004630CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Liu CR, Chang CR, Chern Y, Wang TH, Hsieh WC, Shen WC, Chang CY, Chu IC, Deng N, Cohen SN, Cheng TH (2012) Spt4 is selectively required for transcription of extended trinucleotide repeats. Cell 148(4):690–701CrossRefPubMedGoogle Scholar
  22. 22.
    Woodman B, Butler R, Landles C, Lupton MK, Tse J, Hockly E, Moffitt H, Sathasivam K, Bates GP (2007) The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes. Brain Res Bull 72(2–3):83–97CrossRefPubMedGoogle Scholar
  23. 23.
    Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, Ren S, Li XJ, Albin RL, Detloff PJ (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10(2):137–144CrossRefGoogle Scholar
  24. 24.
    Sathasivam K, Neueder A, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RL, Roos RA, Howland D, Detloff PJ, Housman DE, Bates GP (2013) Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A 110(6):2366–2370CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cho S, Hoang A, Sinha R, Zhong XY, Fu XD, Krainer AR, Ghosh G (2011) Interaction between the RNA binding domains of Ser-Arg splicing factor 1 and U1-70 K snRNP protein determines early spliceosome assembly. Proc Natl Acad Sci U S A 108(20):8233–8238CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kaida D, Berg MG, Younis I, Kasim M, Singh LN, Wan L, Dreyfuss G (2010) U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468(7324):664–668CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Berg MG, Singh LN, Younis I, Liu Q, Pinto AM, Kaida D, Zhang Z, Cho S, Sherrill-Mix S, Wan L, Dreyfuss G (2012) U1 snRNP determines mRNA length and regulates isoform expression. Cell 150(1):53–64CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Menalled LB, Kudwa AE, Miller S, Fitzpatrick J, Watson-Johnson J, Keating N, Ruiz M, Mushlin R, Alosio W, McConnell K, Connor D, Murphy C, Oakeshott S, Kwan M, Beltran J, Ghavami A, Brunner D, Park LC, Ramboz S, Howland D (2012) Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington’s disease: zQ175. PLoS ONE 7(12):e49838CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, Duyao MP, Vrbanac V, Weaver M, Gusella JF, Joyner AL, MacDonald ME (1999) Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse. Hum Mol Genet 8(1):115–122CrossRefGoogle Scholar
  30. 30.
    White JK, Auerbach W, Duyao MP, Vonsattel JP, Gusella JF, Joyner AL, MacDonald ME (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet 17(4):404–410CrossRefPubMedGoogle Scholar
  31. 31.
    Hughes AC, Mort M, Elliston L, Thomas RM, Brooks SP, Dunnett SB, Jones L (2014) Identification of novel alternative splicing events in the huntingtin gene and assessment of the functional consequences using structural protein homology modelling. J Mol Biol 426(7):1428–1438CrossRefPubMedGoogle Scholar
  32. 32.
    Mort M, Carlisle FA, Waite AJ, Elliston L, Allen ND, Jones L, Hughes AC (2015) Huntingtin exists as multiple splice forms in human brain. J Huntington’s Dis 4(2):161–171CrossRefGoogle Scholar
  33. 33.
    Ruzo A, Ismailoglu I, Popowski M, Haremaki T, Croft GF, Deglincerti A, Brivanlou AH (2015) Discovery of novel isoforms of huntingtin reveals a new hominid-specific exon. PLoS ONE 10(5):e0127687CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Gipson TA, Neueder A, Wexler NS, Bates GP, Housman D (2013) Aberrantly spliced HTT, a new player in Huntington’s disease pathogenesis. RNA Biol 10(11):1647–1652CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Genetic Modifiers of Huntington’s Disease C (2015) Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 162(3):516–526Google Scholar
  36. 36.
    Larson E, Fyfe I, Morton AJ, Monckton DG (2015) Age-, tissue-and length-dependent bidirectional somatic CAG*CTG repeat instability in an allelic series of R6/2 Huntington disease mice. Neurobiology of disease 76:98–111CrossRefGoogle Scholar
  37. 37.
    Aronin N, DiFiglia M (2014) Huntingtin-lowering strategies in Huntington’s disease: antisense oligonucleotides, small RNAs, and gene editing. Movement disorders: official journal of the Movement Disorder Society 29(11):1455–1461CrossRefGoogle Scholar
  38. 38.
    Wild EJ, Tabrizi SJ (2014) Targets for future clinical trials in Huntington’s disease: what’s in the pipeline? Movement Disorders. Official J Mov Disord Soc 29(11):1434–1445CrossRefGoogle Scholar
  39. 39.
    Carroll JB, Warby SC, Southwell AL, Doty CN, Greenlee S, Skotte N, Hung G, Bennett CF, Freier SM, Hayden MR (2011) Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene/allele-specific silencing of mutant huntingtin. Mol Ther J Am Soc Gene Ther 19(12):2178–2185CrossRefGoogle Scholar
  40. 40.
    Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, Yang L, Kotin RM, Paulson HL, Davidson BL (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 102(16):5820–5825CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Stanek LM, Sardi SP, Mastis B, Richards AR, Treleaven CM, Taksir T, Misra K, Cheng SH, Shihabuddin LS (2014) Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington’s disease. Hum Gene Ther 25(5):461–474CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Trager U, Andre R, Lahiri N, Magnusson-Lind A, Weiss A, Grueninger S, McKinnon C, Sirinathsinghji E, Kahlon S, Pfister EL, Moser R, Hummerich H, Antoniou M, Bates GP, Luthi-Carter R, Lowdell MW, Bjorkqvist M, Ostroff GR, Aronin N, Tabrizi SJ (2014) HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFkappaB pathway dysregulation. Brain J Neurol 137(Pt 3):819–833CrossRefGoogle Scholar
  43. 43.
    Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, Artates JW, Weiss A, Cheng SH, Shihabuddin LS, Hung G, Bennett CF, Cleveland DW (2012) Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74(6):1031–1044CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pelechano V, Steinmetz LM (2013) Gene regulation by antisense transcription. Nat Rev Genet 14(12):880–893CrossRefPubMedGoogle Scholar
  45. 45.
    Chung DW, Rudnicki DD, Yu L, Margolis RL (2011) A natural antisense transcript at the Huntington’s disease repeat locus regulates HTT expression. Hum Mol Genet 20(17):3467–3477CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Philips AV, Timchenko LT, Cooper TA (1998) Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280(5364):737–741CrossRefGoogle Scholar
  47. 47.
    Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thornton CA, Esson D, Timmers AM, Hauswirth WW, Swanson MS (2003) A muscleblind knockout model for myotonic dystrophy. Science 302(5652):1978–1980CrossRefPubMedGoogle Scholar
  48. 48.
    Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscle blind proteins to (CUG)(n) expansions associated with myotonic dystrophy. The EMBO journal 19(17):4439–4448CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Jog SP, Paul S, Dansithong W, Tring S, Comai L, Reddy S (2012) RNA splicing is responsive to MBNL1 dose. PLoS ONE 7(11):e48825CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Li X, Kazan H, Lipshitz HD, Morris QD (2014) Finding the target sites of RNA-binding proteins. Wiley Interdisciplinary Rev RNA 5(1):111–130CrossRefGoogle Scholar
  51. 51.
    de Mezer M, Wojciechowska M, Napierala M, Sobczak K, Krzyzosiak WJ (2011) Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res 39(9):3852–3863CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Yuan Y, Compton SA, Sobczak K, Stenberg MG, Thornton CA, Griffith JD, Swanson MS (2007) Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs. Nucleic Acids Res 35(16):5474–5486CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Mykowska A, Sobczak K, Wojciechowska M, Kozlowski P, Krzyzosiak WJ (2011) CAG repeats mimic CUG repeats in the misregulation of alternative splicing. Nucleic Acids Res 39(20):8938–8951CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Neueder A, Bates GP (2014) A common gene expression signature in Huntington’s disease patient brain regions. BMC Med Genomics 7:60CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Sun X, Li PP, Zhu S, Cohen R, Marque LO, Ross CA, Pulst SM, Chan HY, Margolis RL, Rudnicki DD (2015) Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Scientific reports 5:12521CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Wilson RC, Doudna JA (2013) Molecular mechanisms of RNA interference. Annual Rev Biophysics 42:217–239CrossRefGoogle Scholar
  57. 57.
    Krol J, Fiszer A, Mykowska A, Sobczak K, de Mezer M, Krzyzosiak WJ (2007) Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol Cell 25(4):575–586CrossRefPubMedGoogle Scholar
  58. 58.
    Banez-Coronel M, Porta S, Kagerbauer B, Mateu-Huertas E, Pantano L, Ferrer I, Guzman M, Estivill X, Marti E (2012) A pathogenic mechanism in Huntington’s disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet 8(2):e1002481CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Valor LM (2015) Transcription, epigenetics and ameliorative strategies in Huntington’s disease: a genome-wide perspective. Mol Neurobiol 51(1):406–423CrossRefPubMedGoogle Scholar
  60. 60.
    Benn CL, Sun T, Sadri-Vakili G, McFarland KN, DiRocco DP, Yohrling GJ, Clark TW, Bouzou B, Cha JH (2008) Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J Neurosci 28(42):10720–10733CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Yin X, Jin N, Gu J, Shi J, Zhou J, Gong CX, Iqbal K, Grundke-Iqbal I, Liu F (2012) Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10 inclusion. J Biol Chem 287(36):30497–30506CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Medina M, Hernandez F, Avila J (2016) New Features about Tau Function and Dysfunction. Biomolecules 6(2)CrossRefGoogle Scholar
  63. 63.
    Qian W, Liu F (2014) Regulation of alternative splicing of tau exon 10. Neuroscience Bulletin 30(2):367–377CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Fernandez-Nogales M, Cabrera JR, Santos-Galindo M, Hoozemans JJ, Ferrer I, Rozemuller AJ, Hernandez F, Avila J, Lucas JJ (2014) Huntington’s disease is a four-repeat tauopathy with tau nuclear rods. Nat Med 20(8):881–885CrossRefPubMedGoogle Scholar
  65. 65.
    Blum D, Herrera F, Francelle L, Mendes T, Basquin M, Obriot H, Demeyer D, Sergeant N, Gerhardt E, Brouillet E, Buee L, Outeiro TF (2015) Mutant huntingtin alters Tau phosphorylation and subcellular distribution. Hum Mol Genet 24(1):76–85CrossRefPubMedGoogle Scholar
  66. 66.
    Vuono R, Winder-Rhodes S, de Silva R, Cisbani G, Drouin-Ouellet J, Network RIotEHsD, Spillantini MG, Cicchetti F, Barker RA (2015) The role of tau in the pathological process and clinical expression of Huntington’s disease. Brain J Neurol 138(Pt 7):1907–1918CrossRefGoogle Scholar
  67. 67.
    Lin L, Park JW, Ramachandran S, Zhang Y, Tseng YT, Shen S, Waldvogel HJ, Curtis MA, Faull RL, Troncoso JC, Ross CA, Davidson BL, Xing Y (2016) Transcriptome sequencing reveals aberrant alternative splicing in Huntington’s disease. Hum Mol GenetCrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44(6):559–577CrossRefGoogle Scholar
  69. 69.
    Zuccato C, Belyaev N, Conforti P, Ooi L, Tartari M, Papadimou E, MacDonald M, Fossale E, Zeitlin S, Buckley N, Cattaneo E (2007) Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. J Neurosci 27(26):6972–6983CrossRefPubMedGoogle Scholar
  70. 70.
    Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35(1):76–83CrossRefPubMedGoogle Scholar
  71. 71.
    Schiffer D, Caldera V, Mellai M, Conforti P, Cattaneo E, Zuccato C (2014) Repressor element-1 silencing transcription factor (REST) is present in human control and Huntington’s disease neurones. Neuropathol Appl Neurobiol 40(7):899–910CrossRefPubMedGoogle Scholar
  72. 72.
    Shimojo M (2008) Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150 Glued. J Biol Chem 283(50):34880–34886CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Soldati C, Bithell A, Johnston C, Wong KY, Stanton LW, Buckley NJ (2013) Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington’s disease. J Neurochem 124(3):418–430CrossRefPubMedGoogle Scholar
  74. 74.
    Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293(5529):493–498CrossRefPubMedGoogle Scholar
  75. 75.
    Gharami K, Xie Y, An JJ, Tonegawa S, Xu B (2008) Brain-derived neurotrophic factor over-expression in the forebrain ameliorates Huntington’s disease phenotypes in mice. J Neurochem 105(2):369–379CrossRefPubMedGoogle Scholar
  76. 76.
    Xie Y, Hayden MR, Xu B (2010) BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci 30(44):14708–14718CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Conforti P, Mas Monteys A, Zuccato C, Buckley NJ, Davidson B, Cattaneo E (2013) In vivo delivery of DN:REST improves transcriptional changes of REST-regulated genes in HD mice. Gene Ther 20(6):678–685CrossRefPubMedGoogle Scholar
  78. 78.
    Soldati C, Bithell A, Conforti P, Cattaneo E, Buckley NJ (2011) Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington’s disease. J Neurochem 116(3):415–425CrossRefPubMedGoogle Scholar
  79. 79.
    Johnson R, Zuccato C, Belyaev ND, Guest DJ, Cattaneo E, Buckley NJ (2008) A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiology Dis 29(3):438–445CrossRefGoogle Scholar
  80. 80.
    Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. J Neurosci 28(53):14341–14346CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Qiu L, Tan EK, Zeng L (2015) microRNAs and Neurodegenerative Diseases. Adv Exp Med Biol 888:85–105CrossRefPubMedGoogle Scholar
  82. 82.
    Cohen JE, Lee PR, Chen S, Li W, Fields RD (2011) MicroRNA regulation of homeostatic synaptic plasticity. Proc Natl Acad Sci U S A 108(28):11650–11655CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Lee ST, Chu K, Im WS, Yoon HJ, Im JY, Park JE, Park KH, Jung KH, Lee SK, Kim M, Roh JK (2011) Altered microRNA regulation in Huntington’s disease models. Exp Neurol 227(1):172–179CrossRefPubMedGoogle Scholar
  84. 84.
    Kocerha J, Xu Y, Prucha MS, Zhao D, Chan AW (2014) microRNA-128a dysregulation in transgenic Huntington’s disease monkeys. Molecular brain 7:46CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Hoss AG, Kartha VK, Dong X, Latourelle JC, Dumitriu A, Hadzi TC, Macdonald ME, Gusella JF, Akbarian S, Chen JF, Weng Z, Myers RH (2014) MicroRNAs located in the Hox gene clusters are implicated in huntington’s disease pathogenesis. PLoS Genet 10(2):e1004188CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Hoss AG, Labadorf A, Latourelle JC, Kartha VK, Hadzi TC, Gusella JF, MacDonald ME, Chen JF, Akbarian S, Weng Z, Vonsattel JP, Myers RH (2015) miR-10b-5p expression in Huntington’s disease brain relates to age of onset and the extent of striatal involvement. BMC Med Genomics 8:10CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Marti E, Pantano L, Banez-Coronel M, Llorens F, Minones-Moyano E, Porta S, Sumoy L, Ferrer I, Estivill X (2010) A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing. Nucleic Acids Res 38(20):7219–7235CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Gaughwin PM, Ciesla M, Lahiri N, Tabrizi SJ, Brundin P, Bjorkqvist M (2011) Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington’s disease. Hum Mol Genet 20(11):2225–2237CrossRefPubMedGoogle Scholar
  89. 89.
    Mastrokolias A, Ariyurek Y, Goeman JJ, van Duijn E, Roos RA, van der Mast RC, van Ommen GB, den Dunnen JT, t Hoen PA, van Roon-Mom WM (2015) Huntington’s disease biomarker progression profile identified by transcriptome sequencing in peripheral blood. European J Human Genet EJHG 23(10):1349–1356CrossRefGoogle Scholar
  90. 90.
    Azlan A, Dzaki N, Azzam G (2016) Argonaute: the executor of small RNA function. J Genet Genomics = Yi chuan xue baoCrossRefGoogle Scholar
  91. 91.
    Savas JN, Makusky A, Ottosen S, Baillat D, Then F, Krainc D, Shiekhattar R, Markey SP, Tanese N (2008) Huntington’s disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies. Proc Natl Acad Sci U S A 105(31):10820–10825CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Jain S, Parker R (2013) The discovery and analysis of P Bodies. Adv Exp Med Biol 768:23–43CrossRefPubMedGoogle Scholar
  93. 93.
    Krauss S, Griesche N, Jastrzebska E, Chen C, Rutschow D, Achmuller C, Dorn S, Boesch SM, Lalowski M, Wanker E, Schneider R, Schweiger S (2013) Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1-PP2A protein complex. Nature communications 4:1511CrossRefPubMedGoogle Scholar
  94. 94.
    Cleary JD, Ranum LP (2014) Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Curr Opin Genet Dev 26:6–15CrossRefPubMedGoogle Scholar
  95. 95.
    Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, Nan Z, Forster C, Low WC, Schoser B, Somia NV, Clark HB, Schmechel S, Bitterman PB, Gourdon G, Swanson MS, Moseley M, Ranum LP (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108(1):260–265CrossRefPubMedGoogle Scholar
  96. 96.
    Banez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, Pletnikova O, Borchelt DR, Ross CA, Margolis RL, Yachnis AT, Troncoso JC, Ranum LP (2015) RAN translation in Huntington disease. Neuron 88(4):667–677CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8(3):397–407CrossRefGoogle Scholar
  98. 98.
    Caillet-Boudin ML, Fernandez-Gomez FJ, Tran H, Dhaenens CM, Buee L, Sergeant N (2014) Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy. Frontiers in molecular neuroscience 6:57CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Consortium I, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Sobell Department of Motor Neuroscience, UCL Institute of NeurologyLondonUK

Personalised recommendations