Ataxin-2 Regulates Translation in a New BAC-SCA2 Transgenic Mouse Model

English version České info

Spinocerebellar ataxia type 2 (SCA2) is an inherited neurodegenerative disorder leading to predominant loss of Purkinje cells in the cerebellum and impairment of motor coordination. The mutation is expansion of a protein domain consisting of a stretch of glutamine amino acids. We generated a mouse model of SCA2 containing the entire human normal or mutant ATXN2 gene using bacterial artificial chromosome (BAC) technology. Mice expressing a BAC with 72 glutamines (BAC-Q72) developed a progressive cerebellar degeneration and motor impairment in contrast to mice carrying the normal human gene (BAC-Q22). We found that even prior to behavioral onset of disease, the abundance of specific messenger RNAs changed using deep RNA-sequencing. One of the mRNAs with early and significant changes was Rgs8. Levels of Rgs8 protein were even further reduced than mRNA levels in BAC-Q72 cerebella suggesting to us that mutant ATXN2 might have a role in mRNA stability and translation. Using a cellular model, we showed that the ATXN2 protein interacted with RGS8 mRNA and that this interaction differed between normal and mutant ATXN2. Presence of mutant ATXN2 resulted in reduced RGS8 protein translation in a cellular model. Our studies describe a mouse model of SCA2 expressing the entire human ATXN2 gene and emphasize the role of ATXN2 in mRNA metabolism.

Vyšlo v časopise: Ataxin-2 Regulates Translation in a New BAC-SCA2 Transgenic Mouse Model. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005182
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005182

Souhrn

Zdroje

1. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, et al. (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14: 269–276. 8896555

2. Zoghbi HY (1995) Spinocerebellar ataxia type 1. Clin Neurosci 3: 5–11. 7614095

3. Matilla-Dueñas A, Ashizawa T, Brice A, Magri S, McFarland KN, et al. (2014) Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias. Cerebellum 13: 269–302. doi: 10.1007/s12311-013-0539-y 24307138

4. Pulst SM, Santos N, Wang D, Yang H, Huynh D, et al. (2005) Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset. Brain 128: 2297–2303. 16000334

5. Shibata H, Huynh DP, Pulst SM (2002) A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet 9: 1303–1313.

6. Ciosk R, DePalma M, Priess JR (2004) ATX-2, the C. elegans ortholog of ataxin 2, functions in translational regulation in the germline. Development 131: 4831–4841. 15342467

7. Satterfield TF, Pallanck LJ (2006) Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes. Hum Mol Genet 15: 2523–2532. 16835262

8. Nonhoff U, Ralser M, Welzel F, Piccini I, Balzereit D, et al. (2007) Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol Biol Cell 18: 1385–1396. 17392519

9. Van de Warrenburg BP, Hendriks H, Durr A, van Zuijlen MC, Stevanin G, et al, (2005) Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch–French cohort. Ann Neurol 57: 505–512. 15747371

10. Kiehl TR, Shibata H and Pulst SM (2000) The ortholog of human ataxin-2 is essential for early embryonic patterning in C. elegans. J Mol Neurosci 15: 231–241. 11303786

11. Aguiar J, Fernandez J, Aguilar A, Mendoza Y, Vazquez M, et al. (2006) Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self-promoter cause specific Purkinje cell degeneration in transgenic mice. Neurosci. Lett 392: 202–206. 16203087

12. Nonis D, Schmidt MH, van de Loo S, Eich F, Dikic I, et al. (2008) Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking. Cell Signal 20: 1725–1739. doi: 10.1016/j.cellsig.2008.05.018 18602463

13. Liu J, Tang TS, Tu H, Nelson O, Herndon E, et al. (2009) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 29: 9148–9162. doi: 10.1523/JNEUROSCI.0660-09.2009 19625506

14. Van de Loo S, Eich F, Nonis D, Auburger G and Nowock J (2009) Ataxin-2 associates with rough endoplasmic reticulum. Exp. Neurol. 215: 110–118. doi: 10.1016/j.expneurol.2008.09.020 18973756

15. Huynh DP, Scoles DR, Nguyen D and Pulst SM (2003) The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI. Hum Mol Genet 12: 2587–2597. 12925569

16. Kiehl TR, Nechiporuk A, Figueroa KP, Keating MT, Huynh DP, et al. (2006) Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochem Biophys Res Commun 339: 17–24. 16293225

17. Lastres-Becker I, Brodesser S, Lütjohann D, Azizov M, Buchmann J, et al. (2008) Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice. Hum Mol Genet 17: 1465–1481. doi: 10.1093/hmg/ddn035 18250099

18. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, et al. (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075. doi: 10.1038/nature09320 20740007

19. Huynh DP, Figueroa K, Hoang N, Pulst SM (2000) Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet 26: 44–50. 10973246

20. Hansen ST, Meera P, Otis TS, Pulst SM (2013) Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet 22: 271–283. doi: 10.1093/hmg/dds427 23087021

21. Damrath E, Heck MV, Gispert S, Azizov M, Nowock J, et al. (2012) ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice. PLoS Genet 8(8): e1002920. doi: 10.1371/journal.pgen.1002920 22956915

22. Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, et al. (2006) Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 38:758–769. 16804541

23. Furrer SA, Mohanachandran MS, Waldherr SM, Chang C, Damian VA, et al. (2011) Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell-autonomous bergmann glia degeneration. J Neurosci 31: 16269–16278. doi: 10.1523/JNEUROSCI.4000-11.2011 22072678

24. Yu-Taeger L, Petrasch-Parwez E, Osmand AP, Redensek A, Metzger S, et al. (2012) A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntingtondisease. J Neurosci 32:15426–15438. doi: 10.1523/JNEUROSCI.1148-12.2012 23115180

25. Cortes CJ, Ling SC, Guo LT, Hung G, Tsunemi T, et al. (2014) Muscle expression of mutant androgen receptor accounts for systemic and motor neurondisease phenotypes in spinal and bulbar muscular atrophy. Neuron 82: 295–307. doi: 10.1016/j.neuron.2014.03.001 24742458

26. Gray M, Shirasaki DI, Cepeda C, André VM, Wilburn B, et al. (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28: 6182–6195. doi: 10.1523/JNEUROSCI.0857-08.2008 18550760

27. Li Y, Liu W, Oo TF, Wang L, Tang Y, et al. (2009) Mutant LRRK2 (R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 12: 826–828. doi: 10.1038/nn.2349 19503083

28. Allen Institute for Brain Science (2014). Allen Human Brain Atlas [Internet]. Available from: http://human.brain-map.org/, and Allen Mouse Brain Atlas [Internet]. Available from: http://mouse.brain-map.org/.

29. Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR, et al. (2008) Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135: 749–762. doi: 10.1016/j.cell.2008.10.029 19013282

30. Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, et al. (2004) Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system. Mol Brain Res 122: 24–34. 14992813

31. Itoh M, Odagiri M, Abe H, Saitoh O (2001) RGS8 protein is distributed in dendrites and cell body of cerebellar Purkinje cell. Biochem Biophys Res Commun. 287: 223–228. 11549278

32. Maity B, Stewart A, Yang J, Loo L, Sheff D, et al. (2012) Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling. J Biol Chem 287: 4972–4981. doi: 10.1074/jbc.M111.297218 22179605

33. Blundell J, Hoang CV, Potts B, Gold SJ, Powell CM (2008) Motor coordination deficits in mice lacking RGS9. Brain Res 1190: 78–85. 18073128

34. Neuwald AF, Koonin EV (1998) Ataxin-2, global regulators of bacterial gene expression, and spliceosomal snRNP proteins share a conserved domain. J Mol Med (Berl) 76: 3–5.

35. Achsel T, Stark H, Lührmann R (2001) The Sm domain is an ancient RNA-binding motif with oligo(U) specificity. Proc Natl Acad Sci U S A 98: 3685–3689. 11259661

36. Albrecht M, Golatta M, Wüllner U, Lengauer T (2004) Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem 271: 3155–3170. 15265035

37. Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, et al. (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82: 937–948. 7553854

38. Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, et al. (1996) Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13: 196–202. 8640226

39. Torashima T, Koyama C, Iizuka A, Mitsumura K, Takayama K, et al. (2008) Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia. EMBO Rep 9: 393–399. doi: 10.1038/embor.2008.31 18344973

40. Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, et al. (2004) A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci 24: 10266–10279. 15537899

41. Colomer Gould VF, Goti D, Pearce D, Gonzalez GA, Gao H, et al. (2007) A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiol Dis 27: 362–369. 17632007

42. Lorenzetti D, Watase K, Xu B, Matzuk MM, Orr HT, et al. (2000) Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus. Hum Mol Genet 9: 779–785. 10749985

43. Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, et al. (2002) A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34: 905–919. 12086639

44. Van Raamsdonk JM, Gibson WT, Pearson J, Murphy Z, Lu G, et al. (2006) Body weight is modulated by levels of full-length huntingtin. Hum Mol Genet 15: 1513–1523. 16571604

45. Huang S, Ling JJ, Yang S, Li XJ, Li S (2011) Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor. Brain 134:1943–1958. doi: 10.1093/brain/awr146 21705419

46. Huynh DP, Maalouf M, Silva AJ, Schweizer FE, Pulst SM (2009) Dissociated fear and spatial learning in mice with deficiency of ataxin-2. PLoS One 4(7): e6235. doi: 10.1371/journal.pone.0006235 19617910

47. Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, et al. (2005) Energy balance in early-stage Huntington disease. Am J Clin Nutr 81: 1335–1341. 15941884

48. Trejo A, Tarrats RM, Alonso ME, Boll MC, Ochoa A, et al. (2004) Assessment of the nutrition status of patients with Huntington's disease. Nutrition 20: 192–196. 14962685

49. Chang YC, Lin CY, Hsu CM, Lin HC, Chen YH, et al. (2011) Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17. J Neurochem 118: 288–303. doi: 10.1111/j.1471-4159.2011.07304.x 21554323

50. Luthi-Carter R, Strand AD, Hanson SA, Kooperberg C, Schilling G, et al. (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects. Hum Mol Genet 11: 1927–1937. 12165555

51. Chou AH, Yeh TH, Ouyang P, Chen YL, Chen SY, et al. (2008) Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis 31: 89–101. doi: 10.1016/j.nbd.2008.03.011 18502140

52. Chou AH, Chen CY, Chen SY, Chen WJ, Chen YL, et al. (2010) Polyglutamine-expanded ataxin-7 causes cerebellar dysfunction by inducing transcriptional dysregulation. Neurochem Int 56: 329–339. doi: 10.1016/j.neuint.2009.11.003 19909779

53. Gatchel JR, Watase K, Thaller C, Carson JP, Jafar-Nejad P, et al. (2008) The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. Proc Natl Acad Sci U S A. 105: 1291–1296. doi: 10.1073/pnas.0711257105 18216249

54. Crespo-Barreto J, Fryer JD, Shaw CA, Orr HT, Zoghbi HY (2010) Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genet 6: e1001021. doi: 10.1371/journal.pgen.1001021 20628574

55. Friedrich B, Euler P, Ziegler R, Kuhn A, Landwehrmeyer BG, et al. (2012) Comparative analyses of Purkinje cell gene expression profiles reveal shared molecular abnormalities in models of different polyglutamine diseases. Brain Res 1481: 37–48. doi: 10.1016/j.brainres.2012.08.005 22917585

56. Saitoh O, Kubo Y, Miyatani Y, Asano T, Nakata H (1997) RGS8 accelerates G-protein-mediated modulation of K+ currents. Nature 390: 525–529. 9394004

57. Kuwata H, Nakao K, Harada T, Matsuda I, Aiba A (2008) Generation of RGS8 null mutant mice by Cre/loxP system. Kobe J Med Sci 53: 275–281. 18762722

58. Kasumu AW, Liang X, Egorova P, Vorontsova D, Bezprozvanny I (2012) Chronic suppression of inositol 1,4,5-triphosphate receptor-mediated calcium signaling in cerebellar purkinje cells alleviates pathological phenotype in spinocerebellar ataxia 2 mice. J Neurosci 32: 12786–12796. doi: 10.1523/JNEUROSCI.1643-12.2012 22973002

59. Lim C, Allada R (2013) ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila. Science 340: 875–879. doi: 10.1126/science.1234785 23687047

60. Zhang Y, Ling J, Yuan C, Dubruille R, Emery P (2013) A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science 340: 879–882. doi: 10.1126/science.1234746 23687048

61. Kahvejian A, Svitkin YV, Sukarieh R, M'Boutchou MN, Sonenberg N (2005) Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms. Genes Dev 19:104–113. 15630022

62. Polymenidou M, Cleveland DW (2011) The seeds of neurodegeneration: prion-like spreading in ALS. Cell 147: 498–508. doi: 10.1016/j.cell.2011.10.011 22036560

63. Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, et al. (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14: 452–458. doi: 10.1038/nn.2778 21358640

64. Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, et al. (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738. doi: 10.1172/JCI44867 21206091

65. Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19: R46–64. doi: 10.1093/hmg/ddq137 20400460

66. Matera AG (1999) RNA splicing: more clues from spinal muscular atrophy. Curr Biol 9: R140–142. 10074419

67. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, et al. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80: 155–165. 7813012

68. Antar LN, Li C, Zhang H, Carroll RC, Bassell GJ (2006) Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol Cell Neurosci 32: 37–48. 16631377

69. Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60: 201–214. doi: 10.1016/j.neuron.2008.10.004 18957214

70. Broadie K, Pan L (2005) Translational complexity of the fragile x mental retardation protein: insights from the fly. Mol Cell 17: 757–759. 15780932

71. Eulalio A, Behm-Ansmant I., and Izaurralde E. (2007) P bodies; at the crossroads of post-transcriptional pathways. Nat Rev Mol Cell Biol 8: 9–22. 17183357

72. Buchan JR and Parker R (2009) Eukaryotic stress granules: the ins and outs of translation. Mol Cell 36: 932–941. doi: 10.1016/j.molcel.2009.11.020 20064460

73. Neuenschwander AG, Thai KK, Figueroa KP, Pulst SM (2014) Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis. JAMA Neurol 71: 1529–1534. doi: 10.1001/jamaneurol.2014.2082 25285812

74. Tazen S, Figueroa K, Kwan JY, Goldman J, Hunt A, et al. (2013) Amyotrophic lateral sclerosis and spinocerebellar ataxia type 2 in a family with full CAG repeat expansions of ATXN2. JAMA Neurol 70: 1302–1304. 23959108

75. Lim C, Lee J, Choi C, Kilman VL, Kim J, et al (2011) The novel gene twenty-four defines a critical translational step in the Drosophila clock. Nature 470: 399–403. doi: 10.1038/nature09728 21331043

76. Yang XW, Model P, Heintz N (1997) Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nat Biotechnol 15: 859–865. 9306400

77. Gong S and Yang XW (2005) Modification of bacterial artificial chromosomes (BACs) and preparation of intact BAC DNA for generation of transgenic mice. In: Current Protocol Neuroscience (Crawley JN, Gerfen CR, Rogawski MA, Sibley DR, Skolnick P, Wray S, eds), p5.21.21. New York: Wiley.

78. Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, et al. (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4: P3. 12734009

79. Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57. doi: 10.1038/nprot.2008.211 19131956

80. Paul S, Dansithong W, Jog SP, Holt I, Mittal S, et al. (2011) Expanded CUG repeats dysregulate RNA splicing by altering the stoichiometry of the muscleblind 1 complex. J Biol Chem 286: 38427–38438. doi: 10.1074/jbc.M111.255224 21900255