Ataxin2 functions via CrebA to mediate Huntingtin toxicity in circadian clock neurons

English version

Autoři: Fangke Xu ^aff001; Elzbieta Kula-Eversole ^aff001; Marta Iwanaszko ^aff002; Chunghun Lim ^aff001; Ravi Allada ^aff001
Působiště autorů: Department of Neurobiology, Northwestern University, Evanston, Illinois, United States of America ^aff001; Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America ^aff002
Vyšlo v časopise: Ataxin2 functions via CrebA to mediate Huntingtin toxicity in circadian clock neurons. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008356
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1008356

Souhrn

Disrupted circadian rhythms is a prominent and early feature of neurodegenerative diseases including Huntington’s disease (HD). In HD patients and animal models, striatal and hypothalamic neurons expressing molecular circadian clocks are targets of mutant Huntingtin (mHtt) pathogenicity. Yet how mHtt disrupts circadian rhythms remains unclear. In a genetic screen for modifiers of mHtt effects on circadian behavior in Drosophila, we discovered a role for the neurodegenerative disease gene Ataxin2 (Atx2). Genetic manipulations of Atx2 modify the impact of mHtt on circadian behavior as well as mHtt aggregation and demonstrate a role for Atx2 in promoting mHtt aggregation as well as mHtt-mediated neuronal dysfunction. RNAi knockdown of the Fragile X mental retardation gene, dfmr1, an Atx2 partner, also partially suppresses mHtt effects and Atx2 effects depend on dfmr1. Atx2 knockdown reduces the cAMP response binding protein A (CrebA) transcript at dawn. CrebA transcript level shows a prominent diurnal regulation in clock neurons. Loss of CrebA also partially suppresses mHtt effects on behavior and cell loss and restoration of CrebA can suppress Atx2 effects. Our results indicate a prominent role of Atx2 in mediating mHtt pathology, specifically via its regulation of CrebA, defining a novel molecular pathway in HD pathogenesis.

Klíčová slova:

RNA interference – Hyperexpression techniques – Neurons – Toxicity – Circadian rhythms – Huntington disease – Circadian oscillators – cDNA libraries

Zdroje

1. Vonsattel JPG, DiFiglia M. Huntington disease. J Neuropath Exp Neur. 1998;57(5):369–84. doi: 10.1097/00005072-199805000-00001 9596408

2. Rosas HD, Liu AK, Hersch S, Glessner M, Ferrante RJ, Salat DH, et al. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology. 2002;58(5):695–701. doi: 10.1212/wnl.58.5.695 11889230

3. Goodman AOG, Barker RA. How vital is sleep in Huntington’s disease? Journal of Neurology. 2010;257(6):882–97. doi: 10.1007/s00415-010-5517-4 20333394

4. Wulff K, Gatti S, Wettstein JG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease PERSPECTIVES. Nature Reviews Neuroscience. 2010;11(8):589–+.

5. Morton AJ, Wood NI, Hastings MH, Hurelbrink C, Barker RA, Maywood ES. Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease (vol 25, pg 157, 2005). Journal of Neuroscience. 2005;25(15):3994-.

6. Pallier PN, Maywood ES, Zheng ZG, Chesham JE, Inyushkin AN, Dyball R, et al. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of huntington’s disease. Journal of Neuroscience. 2007;27(29):7869–78. doi: 10.1523/JNEUROSCI.0649-07.2007 17634381

7. Sheeba V, Fogle KJ, Holmes TC. Persistence of Morning Anticipation Behavior and High Amplitude Morning Startle Response Following Functional Loss of Small Ventral Lateral Neurons in Drosophila. PLoS One. 2010;5(7). ARTN e11628 doi: 10.1371/journal.pone.0011628 20661292

8. Fisher SP, Black SW, Schwartz MD, Wilk AJ, Chen TM, Lincoln WU, et al. Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington’s disease. Brain. 2013;136(Pt 7):2159–72. Epub 2013/06/27. doi: 10.1093/brain/awt132 23801738.

9. Hunter A, Bordelon Y, Cook I, Leuchter A. QEEG Measures in Huntington’s Disease: A Pilot Study. PLoS Curr. 2010;2:RRN1192. Epub 2010/11/03. doi: 10.1371/currents.RRN1192 21037796

10. Cuturic M, Abramson RK, Vallini D, Frank EM, Shamsnia M. Sleep Patterns in Patients With Huntington’s Disease and Their Unaffected First-Degree Relatives: A Brief Report. Behav Sleep Med. 2009;7(4):245–54. doi: 10.1080/15402000903190215 19787493

11. Diago EB, Perez JP, Lasaosa SS, Alebesque AV, Horta SM, Kulisevsky J, et al. Circadian rhythm and autonomic dysfunction in presymptomatic and early Huntington’s disease. Parkinsonism Relat D. 2017;44:95–100. doi: 10.1016/j.parkreldis.2017.09.013 28935191

12. Goodman AOG, Rogers L, Pilsworth S, McAllister CJ, Shneerson JM, Morton AJ, et al. Asymptomatic Sleep Abnormalities Are a Common Early Feature in Patients with Huntington’s Disease. Curr Neurol Neurosci. 2011;11(2):211–7. doi: 10.1007/s11910-010-0163-x 21103960

13. Kantor S, Szabo L, Varga J, Cuesta M, Morton AJ. Progressive sleep and electroencephalogram changes in mice carrying the Huntington’s disease mutation. Brain. 2013;136:2147–58. doi: 10.1093/brain/awt128 23801737

14. Aziz NA, Pijl H, Frolich M, Schroder-van der Elst JP, van der Bent C, Roelfsema F, et al. Delayed onset of the diurnal melatonin rise in patients with Huntington’s disease. Journal of Neurology. 2009;256(12):1961–5. doi: 10.1007/s00415-009-5196-1 19562249

15. Kalliolia E, Silajdzic E, Nambron R, Hill NR, Doshi A, Frost C, et al. Plasma Melatonin Is Reduced in Huntington’s Disease. Movement Disord. 2014;29(12):1511–5. doi: 10.1002/mds.26003 25164424

16. van Wamelen DJ, Aziz NA, Anink JJ, van Steenhoven R, Angeloni D, Fraschini F, et al. Suprachiasmatic nucleus neuropeptide expression in patients with Huntington’s Disease. Sleep. 2013;36(1):117–25. Epub 2013/01/05. doi: 10.5665/sleep.2314 23288978

17. Park JH, Hall JC. Isolation and chronobiological analysis of a neuropeptide pigment-dispersing factor gene in Drosophila melanogaster. J Biol Rhythms. 1998;13(3):219–28. doi: 10.1177/074873098129000066 9615286

18. Helfrich-Forster C. Robust circadian rhythmicity of Drosophila melanogaster requires the presence of lateral neurons: a brain-behavioral study of disconnected mutants. J Comp Physiol A. 1998;182(4):435–53. doi: 10.1007/S003590050192 9530835

19. Lin Y, Stormo GD, Taghert PH. The neuropeptide pigment-dispersing factor coordinates pacemaker interactions in the Drosophila circadian system. Journal of Neuroscience. 2004;24(36):7951–7. doi: 10.1523/JNEUROSCI.2370-04.2004 15356209

20. Yoshii T, Wulbeck C, Sehadova H, Veleri S, Bichler D, Stanewsky R, et al. The Neuropeptide Pigment-Dispersing Factor Adjusts Period and Phase of Drosophila’s Clock. Journal of Neuroscience. 2009;29(8):2597–610. doi: 10.1523/JNEUROSCI.5439-08.2009 19244536

21. Renn SCP, Park JH, Rosbash M, Hall JC, Taghert PH. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell. 1999;99(7):791–802. doi: 10.1016/s0092-8674(00)81676-1 10619432

22. Allada R, White NE, So WV, Hall JC, Rosbash M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell. 1998;93(5):791–804. Epub 1998/06/18. doi: 10.1016/s0092-8674(00)81440-3 9630223.

23. Rutila JE, Suri V, Le M, So WV, Rosbash M, Hall JC. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell. 1998;93(5):805–14. doi: 10.1016/s0092-8674(00)81441-5 9630224

24. Dubowy C, Sehgal A. Circadian Rhythms and Sleep in Drosophila melanogaster. Genetics. 2017;205(4):1373–97. doi: 10.1534/genetics.115.185157 28360128

25. Lee C, Bae K, Edery I. PER and TIM inhibit the DNA binding activity of a Drosophila CLOCK-CYC/dBMAL1 heterodimer without disrupting formation of the heterodimer: a basis for circadian transcription. Mol Cell Biol. 1999;19(8):5316–25. Epub 1999/07/20. doi: 10.1128/mcb.19.8.5316 10409723

26. Price JL, Blau J, Rothenfluh A, Abodeely M, Kloss B, Young MW. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell. 1998;94(1):83–95. doi: 10.1016/s0092-8674(00)81224-6 9674430

27. Kloss B, Price JL, Saez L, Blau J, Rothenfluh A, Wesley CS, et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase I epsilon. Cell. 1998;94(1):97–107. doi: 10.1016/s0092-8674(00)81225-8 9674431

28. Chiu JC, Ko HW, Edery I. NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed. Cell. 2011;145(3):357–70. Epub 2011/04/26. doi: 10.1016/j.cell.2011.04.002 21514639

29. Ko HW, Jiang J, Edery I. Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature. 2002;420(6916):673–8. doi: 10.1038/nature01272 12442174.

30. Luo WF, Li Y, Tang CHA, Abruzzi KC, Rodriguez J, Pescatore S, et al. CLOCK deubiquitylation by USP8 inhibits CLK/CYC transcription in Drosophila. Genes Dev. 2012;26(22):2536–49. doi: 10.1101/gad.200584.112 23154984

31. Cyran SA, Buchsbaum AM, Reddy KL, Lin MC, Glossop NR, Hardin PE, et al. vrille, Pdp1, and dClock form a second feedback loop in the Drosophila circadian clock. Cell. 2003;112(3):329–41. Epub 2003/02/13. doi: 10.1016/s0092-8674(03)00074-6 12581523.

32. Glossop NR, Houl JH, Zheng H, Ng FS, Dudek SM, Hardin PE. VRILLE Feeds Back to Control Circadian Transcription of Clock in the Drosophila Circadian Oscillator. Neuron. 2003;37(2):249–61. doi: 10.1016/s0896-6273(03)00002-3 12546820.

33. Lim C, Allada R. ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila. Science. 2013;340(6134):875–9. Epub 2013/05/21. doi: 10.1126/science.1234785 23687047.

34. Lim C, Lee J, Choi C, Kilman VL, Kim J, Park SM, et al. The novel gene twenty-four defines a critical translational step in the Drosophila clock. Nature. 2011;470(7334):399–403. Epub 2011/02/19. doi: 10.1038/nature09728 21331043

35. Zhang Y, Ling JL, Yuan CY, Dubruille R, Emery P. A Role for Drosophila ATX2 in Activation of PER Translation and Circadian Behavior. Science. 2013;340(6134):879–82. doi: 10.1126/science.1234746 23687048

36. Lee J, Yoo E, Lee H, Park K, Hur JH, Lim C. LSM12 and ME31B/DDX6 Define Distinct Modes of Posttranscriptional Regulation by ATAXIN-2 Protein Complex in Drosophila Circadian Pacemaker Neurons. Mol Cell. 2017;66(1):129–+. doi: 10.1016/j.molcel.2017.03.004 28388438

37. Lee J, Kim M, Itoh TQ, Lim C. Ataxin-2: A versatile posttranscriptional regulator and its implication in neural function. Wires Rna. 2018;9(6). ARTN e1488 doi: 10.1002/wrna.1488 29869836

38. McCann C, Holohan EE, Das S, Dervan A, Larkin A, Lee JA, et al. The Ataxin-2 protein is required for microRNA function and synapse-specific long-term olfactory habituation. Proc Natl Acad Sci U S A. 2011;108(36):E655–E62. doi: 10.1073/pnas.1107198108 21795609

39. Sudhakaran IP, Hillebrand J, Dervan A, Das S, Holohan EE, Hulsmeier J, et al. FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control. Proc Natl Acad Sci U S A. 2014;111(1):E99–E108. doi: 10.1073/pnas.1309543111 24344294

40. Zhang S, Binari R, Zhou R, Perrimon N. A Genomewide RNA Interference Screen for Modifiers of Aggregates Formation by Mutant Huntingtin in Drosophila. Genetics. 2010;184(4):1165–U491. doi: 10.1534/genetics.109.112516 20100940

41. Romero E, Cha GH, Verstreken P, Ly CV, Hughes RE, Bellen HJ, et al. Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. Neuron. 2008;57(1):27–40. doi: 10.1016/j.neuron.2007.11.025 18184562

42. Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, et al. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington’s disease models. Hum Mol Genet. 2006;15(18):2743–51. doi: 10.1093/hmg/ddl210 16893904

43. Lee WCM, Yoshihara M, Littleton JT. Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington’s disease. Proc Natl Acad Sci U S A. 2004;101(9):3224–9. doi: 10.1073/pnas.0400243101 14978262

44. Weiss KR, Kimura Y, Lee WCM, Littleton JT. Huntingtin Aggregation Kinetics and Their Pathological Role in a Drosophila Huntington’s Disease Model. Genetics. 2012;190(2):581–U488. doi: 10.1534/genetics.111.133710 22095086

45. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo SQ, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585–95. doi: 10.1038/ng1362 15146184

46. Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 2001;413(6857):739–43. Epub 2001/10/19. doi: 10.1038/35099568 11607033.

47. Hockly E, Richon VM, Woodman B, Smith DL, Zhou XB, Rosa E, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci U S A. 2003;100(4):2041–6. doi: 10.1073/pnas.0437870100 12576549

48. Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. Journal of Neuroscience. 2003;23(28):9418–27. doi: 10.1523/JNEUROSCI.23-28-09418.2003 14561870

49. Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC, Slepko N, et al. SUMO modification of Huntingtin and Huntington’s disease pathology. Science. 2004;304(5667):100–4. doi: 10.1126/science.1092194 15064418.

50. Gunawardena S, Her LS, Brusch RG, Laymon RA, Niesman IR, Gordesky-Gold B, et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron. 2003;40(1):25–40. Epub 2003/10/07. doi: 10.1016/s0896-6273(03)00594-4 14527431.

51. Smith GA, Rocha EM, McLean JR, Hayes MA, Izen SC, Isacson O, et al. Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington’s disease. Hum Mol Genet. 2014;23(17):4510–27. doi: 10.1093/hmg/ddu166 24728190

52. Loh DH, Kudo T, Truong D, Wu YF, Colwell CS. The Q175 Mouse Model of Huntington’s Disease Shows Gene Dosage- and Age-Related Decline in Circadian Rhythms of Activity and Sleep. PLoS One. 2013;8(7). ARTN e69993 doi: 10.1371/journal.pone.0069993 23936129

53. Gonzales E, Yin J. Drosophila Models of Huntington’s Disease exhibit sleep abnormalities. PLoS currents. 2010;2. Epub 2010/10/05. doi: 10.1371/currents.RRN1185 20890443

54. Gonzales ED, Tanenhaus AK, Zhang JB, Chaffee RP, Yin JCP. Early-onset sleep defects in Drosophila models of Huntington’s disease reflect alterations of PKA/CREB signaling. Hum Mol Genet. 2016;25(5):837–52. doi: 10.1093/hmg/ddv482 26604145

55. Prakash P, Nambiar A, Sheeba V. Oscillating PDF in termini of circadian pacemaker neurons and synchronous molecular clocks in downstream neurons are not sufficient for sustenance of activity rhythms in constant darkness. PLoS One. 2017;12(5):e0175073. doi: 10.1371/journal.pone.0175073 28558035

56. Xu F, Kula-Eversole E, Iwanaszko M, Hutchison AL, Dinner A, Allada R. Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity. Cell reports. 2019;27(1):59–70 e4. doi: 10.1016/j.celrep.2019.03.015 30943415.

57. Sheeba V, Fogle KJ, Holmes TC. Persistence of morning anticipation behavior and high amplitude morning startle response following functional loss of small ventral lateral neurons in Drosophila. PLoS One. 2010;5(7):e11628. doi: 10.1371/journal.pone.0011628 20661292

58. Auburger G, Sen NE, Meierhofer D, Basak AN, Gitler AD. Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2. Trends Neurosci. 2017;40(8):507–16. doi: 10.1016/j.tins.2017.06.004 28684172

59. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, LopesCendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14(3):269–76. doi: 10.1038/ng1196-269 8896555

60. Helfrich-Forster C, Shafer OT, Wulbeck C, Grieshaber E, Rieger D, Taghert P. Development and morphology of the clock-gene-expressing lateral neurons of Drosophila melanogaster. Journal of Comparative Neurology. 2007;500(1):47–70. doi: 10.1002/cne.21146 17099895

61. Yokoshi M, Li Q, Yamamoto M, Okada H, Suzuki Y, Kawahara Y. Direct Binding of Ataxin-2 to Distinct Elements in 3 ’ UTRs Promotes mRNA Stability and Protein Expression. Mol Cell. 2014;55(2):186–98. doi: 10.1016/j.molcel.2014.05.022 24954906

62. Satterfield TF, Pallanck LJ. Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes. Hum Mol Genet. 2006;15(16):2523–32. doi: 10.1093/hmg/ddl173 16835262

63. Tharun S. Roles of Eukaryotic Lsm Proteins in the Regulation of Mrna Function. Int Rev Cel Mol Bio. 2009;272:149–+. doi: 10.1016/S1937-6448(08)01604-3

64. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. Cag Expansions in a Novel Gene for Machado-Joseph Disease at Chromosome 14q32.1. Nat Genet. 1994;8(3):221–8. doi: 10.1038/ng1194-221 7874163

65. Ichikawa Y, Goto J, Hattori M, Toyoda A, Ishii K, Jeong SY, et al. The genomic structure and expression of MJD, the Machado-Joseph disease gene. J Hum Genet. 2001;46(7):413–22. doi: 10.1007/s100380170060 11450850

66. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–3. doi: 10.1126/science.1134108 17023659

67. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, et al. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol. 2008;63(4):535–8. doi: 10.1002/ana.21344 18288693

68. Kadener S, Villella A, Kula E, Palm K, Pyza E, Botas J, et al. Neurotoxic protein expression reveals connections between the circadian clock and mating behavior in Drosophila. Proc Natl Acad Sci U S A. 2006;103(36):13537–42. Epub 2006/08/30. doi: 10.1073/pnas.0605962103 16938865

69. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668–72. Epub 2008/03/01. doi: 10.1126/science.1154584 18309045.

70. Zhang F, Kang Y, Wang M, Li Y, Xu T, Yang W, et al. Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets. Hum Mol Genet. 2018;27(22):3936–50. Epub 2018/08/15. doi: 10.1093/hmg/ddy292 30107516.

71. Garcia-Arocena D, Hagerman PJ. Advances in understanding the molecular basis of FXTAS. Hum Mol Genet. 2010;19:R83–R9. doi: 10.1093/hmg/ddq166 20430935

72. Kearse MG, Green KM, Krans A, Rodriguez CM, Linsalata AE, Goldstrohm AC, et al. CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins. Mol Cell. 2016;62(2):314–22. doi: 10.1016/j.molcel.2016.02.034 27041225

73. Sudhakaran IP, Hillebrand J, Dervan A, Das S, Holohan EE, Hulsmeier J, et al. FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control. Proc Natl Acad Sci U S A. 2014;111(1):E99–E108. Epub 2013/12/18. doi: 10.1073/pnas.1309543111 24344294

74. Parker R. RNA Degradation in Saccharomyces cerevisae. Genetics. 2012;191(3):671–702. doi: 10.1534/genetics.111.137265 22785621

75. Roy B, Jacobson A. The intimate relationships of mRNA decay and translation. Trends Genet. 2013;29(12):691–9. doi: 10.1016/j.tig.2013.09.002 24091060

76. Mizrak D, Ruben M, Myers GN, Rhrissorrakrai K, Gunsalus KC, Blau J. Electrical Activity Can Impose Time of Day on the Circadian Transcriptome of Pacemaker Neurons. Current Biology. 2012;22(20):1871–80. doi: 10.1016/j.cub.2012.07.070 22940468

77. Arnulf I, Nielsen J, Lohmann E, Schieffer J, Wild E, Jennum P, et al. Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol-Chicago. 2008;65(4):482–8. doi: 10.1001/archneur.65.4.482 18413470

78. Hi Consortium. Induced Pluripotent Stem Cells from Patients with Huntington’s Disease Show CAG-Repeat-Expansion-Associated Phenotypes. Cell Stem Cell. 2012;11(2):264–78. doi: 10.1016/j.stem.2012.04.027 22748968

79. Giles P, Elliston L, Higgs GV, Brooks SP, Dunnett SB, Jones L. Longitudinal analysis of gene expression and behaviour in the HdhQ150 mouse model of Huntington’s disease. Brain Res Bull. 2012;88(2–3):199–209. doi: 10.1016/j.brainresbull.2011.10.001 22001697

80. Lastres-Becker I, Rub U, Auburger G. Spinocerebellar ataxia 2 (SCA2). Cerebellum. 2008;7(2):115–24. doi: 10.1007/s12311-008-0019-y 18418684

81. Tuin I, Voss U, Kang JS, Kessler K, Rub U, Nolte D, et al. Stages of sleep pathology in spinocerebellar ataxia type 2 (SCA2). Neurology. 2006;67(11):1966–72. doi: 10.1212/01.wnl.0000247054.90322.14 17159102

82. Boesch SM, Frauscher B, Brandauer E, Wenning GK, Hogl B, Poewe W. Disturbance of rapid eye movement sleep in spinocerebellar ataxia type 2. Movement Disord. 2006;21(10):1751–4. doi: 10.1002/mds.21036 16830308

83. Rodriguez-Labrada R, Velazquez-Perez L, Ochoa NC, Polo LG, Valencia RH, Cruz GS, et al. Subtle Rapid Eye Movement Sleep Abnormalities in Presymptomatic Spinocerebellar Ataxia Type 2 Gene Carriers. Movement Disord. 2011;26(2):347–50. doi: 10.1002/mds.23409 20960485

84. Al-Ramahi I, Perez AM, Lim J, Zhang MH, Sorensen R, de Haro M, et al. DAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. PLoS Genet. 2007;3(12):2551–64. doi: 10.1371/journal.pgen.0030234 18166084

85. Lessing D, Bonini NM. Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila. PLoS Biol. 2008;6(2):266–74. doi: 10.1371/journal.pbio.0060029 18271626

86. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang XD, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466(7310):1069–U77. doi: 10.1038/nature09320 20740007

87. Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature. 2017;544(7650):367–+. doi: 10.1038/nature22038 28405022

88. Van Blitterswijk M, Mullen B, Heckman MG, Baker MC, DeJesus-Hernandez M, Brown PH, et al. Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol Aging. 2014;35(10). ARTN 2421.e13 doi: 10.1016/j.neurobiolaging.2014.04.016 24866401

89. Lattante S, Millecamps S, Stevanin G, Rivaud-Pechoux S, Moigneu C, Camuzat A, et al. Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders. Neurology. 2014;83(11):990–5. doi: 10.1212/WNL.0000000000000778 25098532

90. Nihei Y, Ito D, Suzuki N. Roles of Ataxin-2 in Pathological Cascades Mediated by TAR DNA-binding Protein 43 (TDP-43) and Fused in Sarcoma (FUS). Journal of Biological Chemistry. 2012;287(49):41310–23. doi: 10.1074/jbc.M112.398099 23048034

91. Ciura S, Sellier C, Campanari ML, Charlet-Berguerand N, Kabashi E. The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway. Autophagy. 2016;12(8):1406–8. doi: 10.1080/15548627.2016.1189070 27245636

92. Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA, Trojanowski JQ, et al. Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. 2014;46(2):152–60. Epub 2013/12/18. doi: 10.1038/ng.2853 24336168

93. Bakthavachalu B, Huelsmeier J, Sudhakaran IP, Hillebrand J, Singh A, Petrauskas A, et al. RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration. Neuron. 2018;98(4):754–+. doi: 10.1016/j.neuron.2018.04.032 29772202

94. van den Heuvel DMA, Harschnitz O, van den Berg LH, Pasterkamp RJ. Taking a risk: a therapeutic focus on ataxin-2 in amyotrophic lateral sclerosis? Trends Mol Med. 2014;20(1):25–35. doi: 10.1016/j.molmed.2013.09.001 24140266