Circadian system disturbances in Huntington’s disease – implications for light therapy

Authors: D. Pačesová 1,2;  S. Moravcová 1,2;  J. Kopřivová 1;  Z. Bendová 1,2
Authors‘ workplace: Národní ústav duševního zdraví, Klecany 1;  Přírodovědecká fakulta, UK Praha 2
Published in: Cesk Slov Neurol N 2019; 82(3): 289-294
Category: Review Article


Huntington disease (HD) is an autosomal-dominant, hereditary neurodegenerative disease with a fatal prognosis. Besides the typical progressive deterioration of motor functions, cognitive and behavioral disorders can also be observed in patients with HD. The most common symptoms also include sleep disorders that seriously affect the quality of life of the patients but also of their relatives and which are being associated with a disrupted circadian system. Stabilization of sleep lenght and quality by strengthening the circadian system could mitigate or suppress many HD symptoms, which, although being a direct result of the disease etiology, can secondarily be heightened by long-term insufficient sleep or circadian system disturbances. Such interventions could lead to slower especially cognitive symptom progression or onset in pre-manifesting patients. Synchronizing bright light therapy, which has already proven useful as a complementary tool for the treatment of affective disorders, as well as some neurodegenerative diseases, could lead to radical improvement of the patients’ quality of life, at least in the early stages of disease development.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.


Huntington disease – circadian system – clock genes – sleep – light therapy


1. 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): 971–983. doi:

2. Saudou F, Humbert S. The biology of Huntingtin. Neuron 2016; 89(5): 910–926. doi: 10.1016/j.neuron.2016.02.003.

3. Fossale E, Seong IS, Coser KR et al. Differential effects of the Huntington’s disease CAG mutation in striatum and cerebellum are quantitative not qualitative. Hum Mol Genet 2011; 20(21): 4258–4267. doi: 10.1093/hmg/ddr355.

4. Langbehn DR, Brinkman RR, Falush D et al. International Huntington’s Disease Collaborative Group. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet 2004; 65(4): 267–277. doi: 10.1111/j.1399-0004.2004.00241.

5. Vonsattel JP, Myers RH, Stevens TJ et al. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 1985; 44(6): 559–577. doi: 10.1097/00005072-198511000-00003.

6. Eddy CM, Parkinson EG, Rickards HE. Changes in mental state and behaviour in Huntington’s disease. Lancet Psychiatry 2016; 3(11): 1079–1086. doi: 10.1016/S2215-0366(16)30144-4.

7. Aziz NA, Anguelova GV, Marinus J et al. Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington’s disease. Parkinsonism Relat Disord 2010; 16(5): 345–350. doi: 10.1016/j.parkreldis.2010.02.009.

8. Morton AJ. Circadian and sleep disorder in Huntington’s disease. Exp Neurol 2013; 243: 34–44. doi: 10.1016/j.expneurol.2012.10.014.

9. Morton AJ, Wood NI, Hastings MH et al. Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease. J Neurosci 2005; 25(1): 157–163. doi: 10.1523/JNEUROSCI.3842-04.2005.

10. Goodman AO, Rogers L, Pilsworth S et al. Asymptomatic sleep abnormalities are a common early feature in patients with Huntington’s disease. Curr Neurol Neurosci Rep 2011; 11(2): 211–217. doi: 10.1007/s11910-010-0163-x.

11. Maywood ES. Synchronization and maintenance of circadian timing in the mammalian clockwork. Eur J Neurosci 2018. doi: 10.1111/ejn.14279.

12. Shirakawa T, Honma S, Honma K. Multiple oscillators in the suprachiasmatic nucleus. Chronobiol Int 2001; 18(3): 371–387. doi: 10.1081/CBI-100103962.

13. Evans JA, Leise TL, Castanon-Cervantes O et al. Dynamic interactions mediated by nonredundant signaling mechanisms couple circadian clock neurons. Neuron 2013; 80(4): 973–983. doi: 10.1016/j.neuron.2013.08.022.

14. Aton SJ, Colwell CS, Harmar AJ et al. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci 2005; 8(4): 476–483. doi: 10.1038/nn1419.

15. Aton SJ, Huettner JE, Straume M et al. GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons. Proc Natl Acad Sci U S A 2006; 103(50): 19188–19193. doi: 10.1073/pnas.0607466103.

16. Harmar AJ, Marston HM, Shen S et al. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 2002; 109(4): 497–508. doi: 10.1016/S0092-8674(02)00736-5.

17. Brown TM, Colwell CS, Waschek JA et al. Disrupted neuronal activity rhythms in the suprachiasmatic nuclei of vasoactive intestinal polypeptide-deficient mice. J Neurophysiol 2007; 97(3): 2553–2558. doi: 10.1152/jn.01206.2006.

18. Colwell CS, Michel S, Itri J et al. Disrupted circadian rhythms in VIP- and PHI-deficient mice. Am J Physiol Regul Integr Comp Physiol 2003; 285(5): R939–R949. doi: 10.1152/ajpregu.00200.2003.

19. Panda S, Antoch MP, Miller BH et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 2002; 109(3): 307–320. doi: 10.1016/S0092-8674(02)00722-5.

20. Ramkisoensing A, Meijer JH. Synchronization of biological clock neurons by light and peripheral feedback systems promotes circadian rhythms and health. Front Neurol 2015; 6:128. doi: 10.3389/fneur.2015.00

21. Golombek DA, Rosenstein RE. Physiology of circadian entrainment. Physiol Rev 2010; 90(3): 1063–1102. doi: 10.1152/physrev.00009.2009.

22. Travnickova-Bendova Z, Cermakian N, Reppert SM et al. Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc Natl Acad Sci U S A 2002; 99(11): 7728–7733. doi: 10.1073/pnas.102075599.

23. Yan L, Silver R. Resetting the brain clock: time course and localization of mPER1 and mPER2 protein expression in suprachiasmatic nuclei during phase shifts. Eur J Neurosci 2004; 19(4): 1105–1109. doi: 10.1111/j.1460-9568.2004.03189.x.

24. Colwell CS. Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci 2011; 12(10): 553–569. doi: 10.1038/nrn3086.

25. Kalliolia E, Silajdžić E, Nambron R et al. Plasma melatonin is reduced in Huntington’s disease. Mov Disord 2014; 29(12): 1511–1515. doi: 10.1002/mds.26003.

26. Baker CR, Domínguez D JF, Stout JC et al. Subjective sleep problems in Huntington’s disease: a pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function. J Neurol Sci 2016; 364: 148–153. doi: 10.1016/j.jns.2016.03.021.

27. Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol 2015;11(7): 401–413. doi: 10.1038/nrneurol.2015.99.

28. Williams RH, Morton AJ, Burdakov D. Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington’s disease. Neurobiol Dis 2011; 42(3): 438–445. doi: 10.1016/j.nbd.2011.02.006.

29. Bellosta Diago E, Pérez Pérez J, Santos Lasaosa S et al. Circadian rhythm and autonomic dysfunction in presymptomatic and early Huntington’s disease. Parkinsonism Relat Disord 2017; 44: 95–100. doi: 10.1016/j.parkreldis.2017.09.013.

30. Aziz NA, Pijl H, Frölich M et al. Delayed onset of the diurnal melatonin rise in patients with Huntington’s disease. J Neurol 2009; 256(12): 1961–1965. doi: 10.1007/s00415-009-5196-1.

31. Aziz NA, Pijl H, Frölich M et al. Increased hypothalamic-pituitary-adrenal axis activity in Huntington’s disease. J Clin Endocrinol Metab 2009; 94(4): 1223–1228. doi: 10.1210/jc.2008-2543.

32. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999; 354(9188): 1435–1439. doi: 10.1016/S0140-6736(99)013­-

33. van Duijn E, Selis MA, Giltay EJ et al. Hypothalamic-pituitary-adrenal axis functioning in Huntington’s disease mutation carriers compared with mutation-negative first-degree controls. Brain Res Bull 2010; 83(5): 232–237. doi: 10.1016/j.brainresbull.2010.08.006.

34. van Wamelen DJ, Aziz NA, Anink JJ et al. Suprachiasmatic nucleus neuropeptide expression in patients with Huntington’s Disease. Sleep 2013; 36(1): 117–125. doi: 10.5665/sleep.2314.

35. van Wamelen DJ, Aziz NA, Anink JJ et al. Paraventricular nucleus neuropeptide expression in Huntington’s disease patients. Brain Pathol 2012; 22(5): 654–661. doi: 10.1111/j.1750-3639.2012.00565.x.

36. Emson PC, Fahrenkrug J, Spokes EG. Vasoactive intestinal polypeptide (VIP): distribution in normal human brain and in Huntington’s disease. Brain Res 1979; 173(1): 174–178. doi: 10.1016/0006-8993(79)91109-0.

37. Bates GP, Mangiarini L, Mahal A et al. Transgenic models of Huntington’s disease. Hum Mol Genet 1997; 6(10): 1633–1637. doi: 10.1093/hmg/6.10.1633.

38. Mangiarini L, Sathasivam K, Seller M 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. doi: 10.1016/S0092-8674(00)81369-0.

39. Lione LA, Carter RJ, Hunt MJ et al. Selective discrimination learning impairments in mice expressing the human Huntington’s disease mutation. J Neurosci 1999; 19(23): 10428–10437. doi: 10.1523/JNEUROSCI.19-23-10428.1999.

40. Björkqvist M, Petersén A, Bacos K et al. Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington’s disease. Hum Mol Genet 2006; 15(10): 1713–1721. doi: 10.1093/hmg/ddl094.

41. Pallier PN, Maywood ES, Zheng Z 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. J Neurosci 2007; 27(29): 7869–7878. doi: 10.1523/JNEUROSCI.0649-07.2007.

42. van Wamelen DJ, Aziz NA, Roos RA et al. Hypothalamic alterations in Huntington’s disease patients: comparison with genetic rodent models. J Neuroendocrinol 2014; 26(11): 761–775. doi: 10.1111/jne.12190.

43. Lin M, Liao P, Chen HM et al. Degeneration of ipRGCs in mouse models of Huntington’s Disease disrupts non-image forming behaviors prior to motor impairment. J Neurosci 2019; 39(8): 1505–1524. doi: 10.1523/JNEUROSCI.0571-18.2018.

44. Fahrenkrug J, Popovic N, Georg B et al. Decreased VIP and VPAC2 receptor expression in the biological clock of the R6/2 Huntington’s disease mouse. J Mol Neurosci 2007; 31(2): 139–148. doi: 10.1385/JMN/31:02:139.

45. Fisher SP, Black SW, Schwartz MD 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): 2159–2172. doi: 10.1093/brain/awt132.

46. Maywood ES, Fraenkel E, McAllister CJ et al. Disruption of peripheral circadian timekeeping in a mouse model of Huntington’s disease and its restoration by temporally scheduled feeding. J Neurosci 2010; 30(30): 10199–10204. doi: 10.1523/JNEUROSCI.1694-10.2010.

47. Ouk K, Hughes S, Pothecary CA et al. Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington’s disease. Hum Mol Genet 2016; 25(24): 5418–5432. doi: 10.1093/hmg/ddw359.

48. Lucas RJ, Hattar S, Takao M et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 2003; 299(5604): 245–247. doi: 10.1126/science.1077293.

49. Paulus W, Schwarz G, Werner A et al. Impairment of retinal increment thresholds in Huntington’s disease. Ann Neurol 1993; 34(4): 574–578. doi: 10.1002/ana.410340411.

50. Kersten HM, Danesh-Meyer HV, Kilfoyle DH et al. Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression. J Neurol 2015; 262(11): 2457–2465. doi: 10.1007/s00415-015-7869-2.

51. Pakhotin P, Harmar AJ, Verkhratsky A et al. VIP receptors control excitability of suprachiasmatic nuclei neurones. Pflugers Arch 2006; 452(1): 7–15. doi: 10.1007/s00424-005-0003-z.

52. Vosko A, van Diepen HC, Kuljis D et al. Role of vasoactive intestinal peptide in the light input to the circadian system. Eur J Neurosci 2015; 42(2): 1839–1848. doi: 10.1111/ejn.12919.

53. Cuesta M, Aungier J, Morton AJ. Behavioral therapy reverses circadian deficits in a transgenic mouse model of Huntington’s disease. Neurobiol Dis 2014; 63: 85–91. doi: 10.1016/j.nbd.2013.11.008.

54. Roenneberg T, Merrow M. The circadian clock and human health. Curr Biol 2016; 26(10): R432–R443. doi: 10.1016/j.cub.2016.04.011.

55. Madrid-Navarro CJ, Sanchez-Galvez R, Martinez-Nicolas A et al. Disruption of circadian rhythms and delirium, sleep impairment and sepsis in critically ill patients. Potential therapeutic implications for increased light-dark contrast and melatonin therapy in an ICU environment. Curr Pham Des 2015; 21(24): 3453–3468. doi: 10.2174/1381612821666150706105602.

56. Dowling GA, Graf CL, Hubbard EM et al. Light treatment for neuropsychiatric behaviors in Alzheimer’s disease. West J Nurs Res 2007; 29(8): 961–975. doi: 10.1177/0193945907303083.

57. Dowling GA, Hubbard EM, Mastick J et al. Effect of morning bright light treatment for rest-activity disruption in institutionalized patients with severe Alzheimer’s disease. Int Psychogeriatr 2005; 17(2): 221–236. doi: 10.1017/S1041610205001584.

58. Willis GL, Turner EJ. Primary and secondary features of Parkinson’s disease improve with strategic exposure to bright light: a case series study. Chronobiol Int
2007; 24(3): 521–537. doi: 10.1080/07420520701420

59. La Morgia C, Ross-Cisneros FN, Sadun AA et al. Retinal ganglion cells and circadian rhythms in Alzheimer’s disease, Parkinson’s disease, and beyond. Front Neurol 2017; 8: 162. doi: 10.3389/fneur.2017.00162.

60. Fifel K, Videnovic A. Chronotherapies for Parkinson’s disease. Prog Neurobiol 2019; 174: 16–27. doi: 10.1016/j.pneurobio.2019.01.002.

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