Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

English version České info

Huntington's disease (HD) is a neurodegenerative disorder for which the mutation results in an extra-long tract of glutamines that causes the huntingtin protein to aggregate. It is characterized by neurological symptoms and brain pathology that is associated with nuclear and cytoplasmic aggregates and with transcriptional dysregulation. Despite the fact that HD has been recognized principally as a neurological disease, there are multiple epidemiological studies showing that HD patients exhibit a high rate of cardiovascular events leading to heart failure. To unravel the cause of cardiac dysfunction in HD models, we employed a wide range of molecular and physiological methods using two well established genetic mouse models of this disease. We found that pre-symptomatic animals developed aberrant gap junction channel expression and a significant deregulation of hypertrophic markers that may predispose them to arrhythmia and an overall change in cardiac function. These changes were accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis in the symptomatic animals. Surprisingly, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation. Therefore, we conclude that the HD-related cardiomyopathy could be driven by altered central autonomic pathways.

Vyšlo v časopise: Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004550
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004550

Souhrn

Zdroje

1. Bates GP, Harper PS, Jones AL, editors (2002) Huntington's Disease. 3rd edition. Oxford: Oxford University Press.

2. StrongTV, TagleDA, ValdesJM, ElmerLW, BoehmK, et al. (1993) Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nat Genet 5 : 259–265.

3. LiSH, SchillingG, YoungWSd, LiXJ, MargolisRL, et al. (1993) Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron 11 : 985–993.

4. ImarisioS, CarmichaelJ, KorolchukV, ChenCW, SaikiS, et al. (2008) Huntington's disease: from pathology and genetics to potential therapies. Biochem J 412 : 191–209.

5. LiW, SerpellLC, CarterWJ, RubinszteinDC, HuntingtonJA (2006) Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein. J Biol Chem 281 : 15916–15922.

6. HarjesP, WankerEE (2003) The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 28 : 425–433.

7. GutekunstCA, LiSH, YiH, MulroyJS, KuemmerleS, et al. (1999) Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J Neurosci 19 : 2522–2534.

8. SathasivamK, HobbsC, TurmaineM, MangiariniL, MahalA, et al. (1999) Formation of polyglutamine inclusions in non-CNS tissue. Hum Mol Genet 8 : 813–822.

9. MoffittH, McPhailGD, WoodmanB, HobbsC, BatesGP (2009) Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington's disease. PLoS One 4: e8025.

10. van der BurgJM, BjorkqvistM, BrundinP (2009) Beyond the brain: widespread pathology in Huntington's disease. Lancet Neurol 8 : 765–774.

11. SorensenSA, FengerK (1992) Causes of death in patients with Huntington's disease and in unaffected first degree relatives. J Med Genet 29 : 911–914.

12. ChiuE, AlexanderL (1982) Causes of death in Huntington's disease. Med J Aust 1 : 153.

13. LanskaDJ, LavineL, LanskaMJ, SchoenbergBS (1988) Huntington's disease mortality in the United States. Neurology 38 : 769–772.

14. AndrichJ, SchmitzT, SaftC, PostertT, KrausP, et al. (2002) Autonomic nervous system function in Huntington's disease. J Neurol Neurosurg Psychiatry 72 : 726–731.

15. HasselbalchSG, ObergG, SorensenSA, AndersenAR, WaldemarG, et al. (1992) Reduced regional cerebral blood flow in Huntington's disease studied by SPECT. J Neurol Neurosurg Psychiatry 55 : 1018–1023.

16. MelikZ, KobalJ, CankarK, StruclM (2012) Microcirculation response to local cooling in patients with Huntington's disease. J Neurol 259 : 921–928.

17. BarKJ, BoettgerMK, AndrichJ, EpplenJT, FischerF, et al. (2008) Cardiovagal modulation upon postural change is altered in Huntington's disease. Eur J Neurol 15 : 869–871.

18. SanbeA, OsinskaH, VillaC, GulickJ, KlevitskyR, et al. (2005) Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy. Proc Natl Acad Sci U S A 102 : 13592–13597.

19. MaloyanA, SanbeA, OsinskaH, WestfallM, RobinsonD, et al. (2005) Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-B-crystallin desmin-related cardiomyopathy. Circulation 112 : 3451–3461.

20. MillucciL, PaccagniniE, GhezziL, BernardiniG, BraconiD, et al. (2011) Different factors affecting human ANP amyloid aggregation and their implications in congestive heart failure. PLoS One 6: e21870.

21. PattisonJS, SanbeA, MaloyanA, OsinskaH, KlevitskyR, et al. (2008) Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure. Circulation 117 : 2743–2751.

22. MangiariniL, SathasivamK, SellerM, CozensB, HarperA, et al. (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 : 493–506.

23. LinCH, Tallaksen-GreeneS, ChienWM, CearleyJA, JacksonWS, et al. (2001) Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum Mol Genet 10 : 137–144.

24. WoodmanB, ButlerR, LandlesC, LuptonMK, TseJ, et al. (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 : 83–97.

25. SathasivamK, NeuederA, GipsonTA, LandlesC, BenjaminAC, et al. (2013) Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A 110 : 2366–2370.

26. WoodNI, SawiakSJ, BuonincontriG, NiuY, KaneAD, et al. (2012) Direct evidence of progressive cardiac dysfunction in a transgenic mouse model of Huntington's disease. J Huntingtons Dis 1 : 57–64.

27. SchneiderM, KostinS, StromCC, AplinM, LyngbaekS, et al. (2007) S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes. Cardiovasc Res 75 : 40–50.

28. ChenHH, MullettSJ, StewartAF (2004) Vgl-4, a novel member of the vestigial-like family of transcription cofactors, regulates alpha1-adrenergic activation of gene expression in cardiac myocytes. J Biol Chem 279 : 30800–30806.

29. ZuccatoC, CattaneoE (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5 : 311–322.

30. BennCL, FoxH, BatesGP (2008) Optimisation of region-specific reference gene selection and relative gene expression analysis methods for pre-clinical trials of Huntington's disease. Mol Neurodegener 3 : 17.

31. KuhnA, GoldsteinDR, HodgesA, StrandAD, SengstagT, et al. (2007) Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet 16 : 1845–1861.

32. StrandAD, AragakiAK, ShawD, BirdT, HoltonJ, et al. (2005) Gene expression in Huntington's disease skeletal muscle: a potential biomarker. Hum Mol Genet 14 : 1863–1876.

33. YaoJA, HussainW, PatelP, PetersNS, BoydenPA, et al. (2003) Remodeling of gap junctional channel function in epicardial border zone of healing canine infarcts. Circ Res 92 : 437–443.

34. GutsteinDE, MorleyGE, TamaddonH, VaidyaD, SchneiderMD, et al. (2001) Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88 : 333–339.

35. LernerDL, YamadaKA, SchuesslerRB, SaffitzJE (2000) Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 101 : 547–552.

36. AndoM, KatareRG, KakinumaY, ZhangD, YamasakiF, et al. (2005) Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation 112 : 164–170.

37. IwanagaK, WakabayashiK, YoshimotoM, TomitaI, SatohH, et al. (1999) Lewy body-type degeneration in cardiac plexus in Parkinson's and incidental Lewy body diseases. Neurology 52 : 1269–1271.

38. RysevaiteK, SaburkinaI, PauzieneN, NoujaimSF, JalifeJ, et al. (2011) Morphologic pattern of the intrinsic ganglionated nerve plexus in mouse heart. Heart Rhythm 8 : 448–454.

39. RichardsonRJ, GrkovicI, AndersonCR (2003) Immunohistochemical analysis of intracardiac ganglia of the rat heart. Cell Tissue Res 314 : 337–350.

40. YangD, WangCE, ZhaoB, LiW, OuyangZ, et al. (2010) Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 19 : 3983–3994.

41. GardJJ, YamadaK, GreenKG, EloffBC, RosenbaumDS, et al. (2005) Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy. Cardiovasc Res 67 : 539–547.

42. OliveM, GoldfarbL, MorenoD, LaforetE, DagvadorjA, et al. (2004) Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies. J Neurol Sci 219 : 125–137.

43. SathasivamK, LaneA, LegleiterJ, WarleyA, WoodmanB, et al. (2010) Identical oligomeric and fibrillar structures captured from the brains of R6/2 and knock-in mouse models of Huntington's disease. Hum Mol Genet 19 : 65–78.

44. HayDG, SathasivamK, TobabenS, StahlB, MarberM, et al. (2004) Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 13 : 1389–1405.

45. LabbadiaJ, CunliffeH, WeissA, KatsyubaE, SathasivamK, et al. (2011) Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J Clin Invest 121 : 3306–3319.

46. YusufSW, SolhpourA, BanchsJ, Lopez-MatteiJC, DurandJB, et al. (2014) Cardiac amyloidosis. Expert Rev Cardiovasc Ther 12 : 265–277.

47. MelkaniGC, TrujilloAS, RamosR, BodmerR, BernsteinSI, et al. (2013) Huntington's disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart. PLoS Genet 9: e1004024.

48. MihmMJ, AmannDM, SchanbacherBL, AltschuldRA, BauerJA, et al. (2007) Cardiac dysfunction in the R6/2 mouse model of Huntington's disease. Neurobiol Dis 25 : 297–308.

49. SchipsTG, WietelmannA, HohnK, SchimanskiS, WaltherP, et al. (2011) FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model. Cardiovasc Res 91 : 587–597.

50. TamakiY, IwanagaY, NiizumaS, KawashimaT, KatoT, et al. (2013) Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts. J Mol Cell Cardiol 57 : 72–81.

51. PereiraVH, CerqueiraJJ, PalhaJA, SousaN (2013) Stressed brain, diseased heart: a review on the pathophysiologic mechanisms of neurocardiology. Int J Cardiol 166 : 30–37.

52. HeierCR, SattaR, LutzC, DiDonatoCJ (2010) Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet 19 : 3906–3918.

53. KobalJ, MelikZ, CankarK, BajrovicFF, MeglicB, et al. (2010) Autonomic dysfunction in presymptomatic and early symptomatic Huntington's disease. Acta Neurol Scand 121 : 392–399.

54. KiriazisH, JenningsNL, DavernP, LambertG, SuY, et al. (2012) Neurocardiac dysregulation and neurogenic arrhythmias in a transgenic mouse model of Huntington's disease. J Physiol 590 : 5845–5860.

55. SaffitzJE (2005) Dependence of electrical coupling on mechanical coupling in cardiac myocytes: insights gained from cardiomyopathies caused by defects in cell-cell connections. Ann N Y Acad Sci 1047 : 336–344.

56. SaffitzJE, HamesKY, KannoS (2007) Remodeling of gap junctions in ischemic and nonischemic forms of heart disease. J Membr Biol 218 : 65–71.

57. DupontE, MatsushitaT, KabaRA, VozziC, CoppenSR, et al. (2001) Altered connexin expression in human congestive heart failure. J Mol Cell Cardiol 33 : 359–371.

58. DaviesSW, TurmaineM, CozensBA, DiFigliaM, SharpAH, et al. (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90 : 537–548.

59. LiH, LiSH, ChengAL, MangiariniL, BatesGP, et al. (1999) Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. Hum Mol Genet 8 : 1227–1236.

60. ChaJH (2007) Transcriptional signatures in Huntington's disease. Prog Neurobiol 83 : 228–248.

61. DoganI, EickhoffSB, SchulzJB, ShahNJ, LairdAR, et al. (2013) Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis. Neurodegener Dis 12 : 23–35.

62. HocklyE, WoodmanB, MahalA, LewisCM, BatesG (2003) Standardization and statistical approaches to therapeutic trials in the R6/2 mouse. Brain Res Bull 61 : 469–479.

63. MielcarekM, BennCL, FranklinSA, SmithDL, WoodmanB, et al. (2011) SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington's disease. PLoS One 6: e27746.

64. HuJ, GeH, NewmanM, LiuK (2012) OSA: a fast and accurate alignment tool for RNA-Seq. Bioinformatics 28 : 1933–1934.

65. AndersS, HuberW (2010) Differential expression analysis for sequence count data. Genome Biol 11: R106.

66. LangfelderP, HorvathS (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9 : 559.

67. LangfelderP, ZhangB, HorvathS (2008) Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut package for R. Bioinformatics. 24 : 719–720.

68. LangfelderP, LuoR, OldhamMC, HorvathS (2011) Is my network module preserved and reproducible? PLoS Comput Biol 7: e1001057.

69. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4 : 44–57.

70. ProttiA, DongX, SirkerA, BotnarR, ShahAM (2012) MRI-based prediction of adverse cardiac remodeling after murine myocardial infarction. Am J Physiol Heart Circ Physiol 303: H309–H314.

71. ProttiA, SirkerA, ShahAM, BotnarR (2010) Late gadolinium enhancement of acute myocardial infarction in mice at 7T: cine-FLASH versus inversion recovery. J Magn Reson Imaging 32 : 878–886.