Targeting CAG repeat RNAs reduces Huntington's disease phenotype independently of huntingtin levels

Journal of Clinical Investigation

Volumn 126, Issue 11, 2016, Pages 4319-4330

  Rué, Laura ^a,b,c   Bañez Corone, Mónica ^a,d,e,f,g   Creus Muncunill, Jordi ^a,b,c   Giralt, Albert ^a,b,c   Alcalá Vida, Rafael ^a,b,c   Mentxaka, Gartze ^d,e,f,g   Kagerbauer, Birgit ^d,e,f,g   Zomeño Abellán, M Teresa ^d,e,f,g   Aranda, Zeus ^d,e,f,g   Venturi, Veronica ^d,e,f,g   Pérez Navarro, Esther ^a,b,c   Estivill, Xavier ^d,e,f,g   Martí, Eullia ^d,e,f,g  

^a UNIVERSITY OF BARCELONA   (Spain)

^b INSTITUT D INVESTIGACIONS BIOMÈDIQUES AUGUST PI I SUNYER IDIBAPS   (Spain)

^c CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED SOBRE ENFERMEDADES NEURODEGENERATIVAS CIBERNED   (Spain)

^d BARCELONA INSTITUTE OF SCIENCE AND TECHNOLOGY   (Spain)

^e UNIVERSITAT POMPEU FABRA   (Spain)

^f CIBER EPIDEMIOLOGÍA Y SALUD PÚBLICA CIBERESP   (Spain)

^g HOSPITAL DEL MAR   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; HUNTINGTIN; LOCKED NUCLEIC ACID; MESSENGER RNA; COMPLEMENTARY RNA; HTT PROTEIN, HUMAN; HTT PROTEIN, MOUSE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CAG REPEAT; CONTROLLED STUDY; EXON; GENE EXPRESSION; HUMAN; HUMAN CELL; HUNTINGTON CHOREA; MOUSE; NEUROPROTECTION; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN BINDING; ANIMAL; BIOSYNTHESIS; DISEASE MODEL; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; HUNTINGTON DISEASE; MALE; METABOLISM; TRANSGENIC MOUSE; TRINUCLEOTIDE REPEAT; TUMOR CELL LINE;

ANIMALS; CELL LINE, TUMOR; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION; HUMANS; HUNTINGTIN PROTEIN; HUNTINGTON DISEASE; MALE; MICE; MICE, TRANSGENIC; RNA, ANTISENSE; TRINUCLEOTIDE REPEATS;

EID: 84994558902     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI83185     Document Type: Article

References (58)

1. A novel gene containing a trinucleotide repeat that is expanded unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993;72(6):971-983
2. Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington's disease. Nat Rev Neurosci. 2005;6(12):919-930
3. Takahashi T, Katada S, Onodera O. Polyglutamine diseases: Where does toxicity come from? What is toxicity? Where are we going? J Mol Cell Biol. 2010;2(4):180-191
4. Labbadia J, Morimoto RI. Huntington's disease: underlying molecular mechanisms and emerging concepts. Trends Biochem Sci. 2013;38(8):378-385
5. Tsoi H, Lau TC, Tsang SY, Lau KF, Chan HY. CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci U S A. 2012;109(33):13428-13433
6. Mezer M, Wojciechowska M, Napierala M, Sobczak K, Krzyzosiak WJ. Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res. 2011;39(9):3852-3863
7. Mykowska A, Sobczak K, Wojciechowska M, Kozlowski P, Krzyzosiak WJ. CAG repeats mimic CUG repeats in the misregulation of alternative splicing. Nucleic Acids Res. 2011;39(20):8938-8951
8. Galka-Marciniak P, Urbanek MO, Krzyzosiak WJ. Triplet repeats in transcripts: structural insights into RNA toxicity. Biol Chem. 2012;393(11):1299-1315
9. Banez-Coronel M, et al. A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet. 2012;8(2):e1002481
10. Jasinska A, et al. Structures of trinucleotide repeats in human transcripts and their functional implications. Nucleic Acids Res. 2003;31(19):5463-5468
11. 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
12. Nalavade R, Griesche N, Ryan DP, Hildebrand S, Krauss S. Mechanisms of RNA-induced toxicity in CAG repeat disorders. Cell Death Dis. 2013;4:e752
13. Zu T, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011;108(1):260-265
14. Matsui M, Corey DR. Allele-selective inhibition of trinucleotide repeat genes. Drug Discov Today. 2012;17(9-10):443-450
15. Fiszer A, Krzyzosiak WJ. Oligonucleotide-based strategies to combat polyglutamine diseases. Nucleic Acids Res. 2014;42(11):6787-6810
16. Hu J, Matsui M, Corey DR. Allele-selective inhibition of mutant huntingtin by peptide nucleic acid-peptide conjugates, locked nucleic acid, and small interfering RNA. Ann N Y Acad Sci. 2009;1175:24-31
17. Gagnon KT, et al. Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry. 2010;49(47):10166-10178
18. Fiszer A, et al. An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases. BMC Mol Biol. 2012;13:6
19. Gines S, Ivanova E, Seong IS, Saura CA, Mac-Donald ME. Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-Daspartate receptor activation in Huntington's disease knock-in striatal cells. J Biol Chem. 2003;278(50):50514-50522
20. Nucifora FC, et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. 2001;291(5512):2423-2428
21. Luthi-Carter R, et al. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum Mol Genet. 2000;9(9):1259-1271
22. Sun Z, Mar N, Meade C, Goldowitz D, Reiner A. Differential changes in striatal projection neurons in R6/2 transgenic mice for Huntington's disease. Neurobiol Dis. 2002;11(3):369-385
23. Torres-Peraza JF, Giralt A, Garcia-Martinez JM, Pedrosa E, Canals JM, Alberch J. Disruption of striatal glutamatergic transmission induced by mutant huntingtin involves remodeling of both postsynaptic density and NMDA receptor signaling. Neurobiol Dis. 2008;29(3):409-421
24. Saavedra A, et al. PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum. Cell Death Differ. 2010;17(2):324-335
25. Saavedra A, et al. Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity. J Neurosci. 2011;31(22):8150-8162
26. Krol J, Fiszer A, Mykowska A, Sobczak K, Mezer M, Krzyzosiak WJ. Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol Cell. 2007;25(4):575-586
27. Lawlor KT, et al. Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neurodegenerative diseases. Hum Mol Genet. 2011;20(19):3757-3768
28. Tsoi H, Chan HY. Expression of expanded CAG transcripts triggers nucleolar stress in Huntington's disease. Cerebellum. 2013;12(3):310-312
29. Hu J, et al. Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat Biotechnol. 2009;27(5):478-484
30. Gagnon KT, et al. Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates. J Am Chem Soc. 2011;133(22):8404-8407
31. Boudreau RL, et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Mol Ther. 2009;17(6):1053-1063
32. Drouet V, et al. Sustained effects of nonallele-specific Huntingtin silencing. Ann Neurol. 2009;65(3):276-285
33. Harper SQ, et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc Natl Acad Sci U S A. 2005;102(16):5820-5825
34. DiFiglia M, et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci U S A. 2007;104(43):17204-17209
35. Kordasiewicz HB, et al. Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron. 2012;74(6):1031-1044
36. Sun X, et al. Phosphorodiamidate morpholino oligomers suppress mutant huntingtin expression and attenuate neurotoxicity. Hum Mol Genet. 2014;23(23):6302-6317
37. Mangiarini L, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996;87(3):493-506
38. Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50:259-293
39. Wojtkowiak-Szlachcic A, et al. Short antisense-locked nucleic acids (all-LNAs) correct alternative splicing abnormalities in myotonic dystrophy. Nucleic Acids Res. 2015;43(6):3318-3331
40. Banez-Coronel M, et al. RAN Translation in Huntington Disease. Neuron. 2015;88(4):667-677
41. Dragatsis I, et al. CAG repeat lengths ≥335 attenuate the phenotype in the R6/2 Huntington's disease transgenic mouse. Neurobiol Dis. 2009;33(3):315-330
42. Mollersen L, Rowe AD, Larsen E, Rognes T, Klungland A. Continuous and periodic expansion of CAG repeats in Huntington's disease R6/1 mice. PLoS Genet. 2010;6(12):e1001242
43. Morton AJ, et al. Paradoxical delay in the onset of disease caused by super-long CAG repeat expansions in R6/2 mice. Neurobiol Dis. 2009;33(3):331-341
44. Giralt A, Saavedra A, Carreton O, Xifro X, Alberch J, Perez-Navarro E. Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease. Hum Mol Genet. 2011;20(21):4232-4247
45. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded unstable on Huntington's disease chromosomes. Cell. 1993;72(6):971-983
46. Giralt A, Carreton O, Lao-Peregrin C, Martin ED, Alberch J. Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction. Mol Neurodegener. 2011;6(1):71
47. Ferrante RJ, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002;22(5):1592-1599
48. Rue L, Lopez-Soop G, Gelpi E, Martinez-Vicente M, Alberch J, Perez-Navarro E. Brain region-and age-dependent dysregulation of p62 and NBR1 in a mouse model of Huntington's disease. Neurobiol Dis. 2013;52:219-228
49. Watson JD, Varley JG, Tomlin SJ, Medbak S, Rees LH, Hinds CJ. Biochemical characterization of circulating Met-enkephalins in canine endotoxin shock. J Endocrinol. 1986;111(2):329-334
50. Brito V, Puigdellivol M, Giralt A, del Toro D, Alberch J, Gines S. Imbalance of p75(NTR)/ TrkB protein expression in Huntington's disease: implication for neuroprotective therapies. Cell Death Dis. 2013;4:e595
51. Ritchie ME, et al. A comparison of background correction methods for two-colour microarrays. Bioinformatics. 2007;23(20):2700-2707
52. Bolstad BM, Irizarry RA, Astrand M, Speed TP. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics. 2003;19(2):185-193
53. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3
54. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57(1), 289-300. http://www.jstor.org/ stable/2346101. Accessed September 29, 2016
55. Gentleman RC, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5(10):R80
56. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-408
57. Steibel JP, Poletto R, Coussens PM, Rosa GJ. A powerful and flexible linear mixed model framework for the analysis of relative quantification RT-PCR data. Genomics. 2009;94(2):146-152
58. Minones-Moyano E, et al. MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet. 2011;20(15):3067-3078