The NADPH Metabolic Network Regulates Human Cardiomyopathy and Reductive Stress in

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Dominant mutations in the alpha-B crystallin (CryAB) gene are responsible for a number of inherited human disorders, including cardiomyopathy, skeletal muscle myopathy, and cataracts. The cellular mechanisms of disease pathology for these disorders are not well understood. Among recent advances is that the disease state can be linked to a disturbance in the oxidation/reduction environment of the cell. In a mouse model, cardiomyopathy caused by the dominant CryAB^R120G missense mutation was suppressed by mutation of the gene that encodes glucose 6-phosphate dehydrogenase (G6PD), one of the cell's primary sources of reducing equivalents in the form of NADPH. Here, we report the development of a Drosophila model for cellular dysfunction caused by this CryAB mutation. With this model, we confirmed the link between G6PD and mutant CryAB pathology by finding that reduction of G6PD expression suppressed the phenotype while overexpression enhanced it. Moreover, we find that expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions, similar to the effects produced in mice and humans, and that reduction of G6PD ameliorated these effects. Finally, to determine whether CryAB pathology responds generally to NADPH levels we tested mutants or RNAi-mediated knockdowns of phosphogluconate dehydrogenase (PGD), isocitrate dehydrogenase (IDH), and malic enzyme (MEN), the other major enzymatic sources of NADPH, and we found that all are capable of suppressing CryAB^R120G pathology, confirming the link between NADP/H metabolism and CryAB.

Vyšlo v časopise: The NADPH Metabolic Network Regulates Human Cardiomyopathy and Reductive Stress in. PLoS Genet 9(6): e32767. doi:10.1371/journal.pgen.1003544
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003544

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Zdroje

1. SelcenD, EngelAG (2011) Myofibrillar myopathies. Handbook of clinical neurology/edited by PJ Vinken and GW Bruyn 101: 143–154.

2. VicartP, CaronA, GuicheneyP, LiZ, PrévostMC, et al. (1998) A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 20: 92–95.

3. GoldfarbLG, DalakasMC (2009) Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. The Journal of Clinical Investigation 119: 1806–1813.

4. BovaMP, YaronO, HuangQ, DingL, HaleyDA, et al. (1999) Mutation R120G in alphaB-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function. Proc Natl Acad Sci U S A 96: 6137–6142.

5. PerngMD, MuchowskiPJ, van DenIP, WuGJ, HutchesonAM, et al. (1999) The cardiomyopathy and lens cataract mutation in alphaB-crystallin alters its protein structure, chaperone activity, and interaction with intermediate filaments in vitro. The Journal of Biological Chemistry 274: 33235–33243.

6. WangX, OsinskaH, KlevitskyR, GerdesAM, NiemanM, et al. (2001) Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice. Circ Res 89: 84–91.

7. RajasekaranNS, ConnellP, ChristiansES, YanLJ, TaylorRP, et al. (2007) Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell 130: 427–439.

8. WinklhoferKF, TatzeltJ, HaassC (2008) The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. The EMBO Journal 27: 336–349.

9. CampioniS, ManniniB, ZampagniM, PensalfiniA, ParriniC, et al. (2010) A causative link between the structure of aberrant protein oligomers and their toxicity. Nature Chemical Biology 6: 140–147.

10. BalchWE, MorimotoRI, DillinA, KellyJW (2008) Adapting proteostasis for disease intervention. Science 319: 916–919.

11. BolognesiB, KumitaJR, BarrosTP, EsbjornerEK, LuheshiLM, et al. (2010) ANS binding reveals common features of cytotoxic amyloid species. ACS Chemical Biology 5: 735–740.

12. LashuelHA, LansburyPTJr (2006) Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Quarterly Reviews of Biophysics 39: 167–201.

13. KayedR, HeadE, ThompsonJL, McIntireTM, MiltonSC, et al. (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486–489.

14. SanbeA, OsinskaH, SaffitzJE, GlabeCG, KayedR, et al. (2004) Desmin-related cardiomyopathy in transgenic mice: a cardiac amyloidosis. Proc Natl Acad Sci U S A 101: 10132–10136.

15. RubinGM, YandellMD, WortmanJR, Gabor MiklosGL, NelsonCR, et al. (2000) Comparative genomics of the eukaryotes. Science 287: 2204–2215.

16. OlsonEN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313: 1922–1927.

17. CammaratoA, AhrensCH, AlayariNN, QeliE, RuckerJ, et al. (2011) A Mighty Small Heart: The Cardiac Proteome of Adult Drosophila melanogaster. PLoS ONE 6: e18497.

18. NeelyGG, KubaK, CammaratoA, IsobeK, AmannS, et al. (2010) A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function. Cell 141: 142–153.

19. PaternostroG, VignolaC, BartschDU, OmensJH, McCullochAD, et al. (2001) Age-associated cardiac dysfunction in Drosophila melanogaster. Circ Res 88: 1053–1058.

20. TickooS, RussellS (2002) Drosophila melanogaster as a model system for drug discovery and pathway screening. Curr Opin Pharmacol 2: 555–560.

21. BierE, BodmerR (2004) Drosophila, an emerging model for cardiac disease. Gene 342: 1–11.

22. LessingD, BoniniNM (2009) Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants. Nat Rev Genet 10: 359–370.

23. ChomaMA, IzattSD, WessellsRJ, BodmerR, IzattJA (2006) Images in cardiovascular medicine: in vivo imaging of the adult Drosophila melanogaster heart with real-time optical coherence tomography. Circulation 114: e35–36.

24. OcorrK, ReevesNL, WessellsRJ, FinkM, ChenHS, et al. (2007) KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging. Proc Natl Acad Sci U S A 104: 3943–3948.

25. OcorrK, AkasakaT, BodmerR (2007) Age-related cardiac disease model of Drosophila. Mech Ageing Dev 128: 112–116.

26. AkasakaT, KlinedinstS, OcorrK, BustamanteEL, KimSK, et al. (2006) The ATP-sensitive potassium (KATP) channel-encoded dSUR gene is required for Drosophila heart function and is regulated by tinman. Proc Natl Acad Sci U S A 103: 11999–12004.

27. WolfMJ, AmreinH, IzattJA, ChomaMA, ReedyMC, et al. (2006) Drosophila as a model for the identification of genes causing adult human heart disease. Proc Natl Acad Sci U S A 103: 1394–1399.

28. Taghli-LamallemO, AkasakaT, HoggG, NudelU, YaffeD, et al. (2008) Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype. Aging Cell 7: 237–249.

29. FischerJA, GinigerE, ManiatisT, PtashneM (1988) GAL4 activates transcription in Drosophila. Nature 332: 853–856.

30. BrandAH, PerrimonN (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401–415.

31. McLendonPM, RobbinsJ (2011) Desmin-Related Cardiomyopathy: An Unfolding Story. American Journal of Physiology Heart and Circulatory Physiology 301: H1220–1228.

32. OcorrK, FinkM, CammaratoA, BernsteinSI, BodmerR (2009) Semi-automated Optical Heartbeat Analysis of Small Hearts. Journal of Visualized Experiments 31: 1435.

33. RørthP, SzaboK, BaileyA, LavertyT, RehmJ, et al. (1998) Systematic gain-of-function genetics in Drosophila. Development 125: 1049–1057.

34. BilenJ, BoniniNM (2005) Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 39: 153–171.

35. LuB, VogelH (2009) Drosophila models of neurodegenerative diseases. Annu Rev Pathol 4: 315–342.

36. McAlisterL, FinkelsteinDB (1980) Heat shock proteins and thermal resistance in yeast. Biochem Biophys Res Commun 93: 819–824.

37. Plesofsky-VigN, BramblR (1985) Heat shock response of Neurospora crassa: protein synthesis and induced thermotolerance. J Bacteriol 162: 1083–1091.

38. LeganSK, RebrinI, MockettRJ, RadyukSN, KlichkoVI, et al. (2008) Overexpression of Glucose-6-phosphate Dehydrogenase Extends the Life Span of Drosophila melanogaster. J Biol Chem 283: 32492–32499.

39. PrevilleX, SalveminiF, GiraudS, ChaufourS, PaulC, et al. (1999) Mammalian small stress proteins protect against oxidative stress through their ability to increase glucose-6-phosphate dehydrogenase activity and by maintaining optimal cellular detoxifying machinery. Exp Cell Res 247: 61–78.

40. MeloniL, MancaMR, LoddoI, CiogliaG, CoccoP, et al. (2008) Glucose-6-phosphate dehydrogenase deficiency protects against coronary heart disease. J Inherit Metab Dis 31: 412–417.

41. CoccoP, ToddeP, ForneraS, MancaMB, MancaP, et al. (1998) Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency. Blood 91: 706–709.

42. LongWK, WilsonSW, FrenkelEP (1967) Associations between red cell glucose-6-phosphate dehydrogenase variants and vascular diseases. Am J Hum Genet 19: 35–53.

43. TueNT, ShimajiK, TanakaN, YamaguchiM (2012) Effect of alphaB-crystallin on protein aggregation in Drosophila. J Biomed Biotechnol 2012: 252049.

44. GoebelHH (1997) Desmin-related myopathies. Curr Opin Neurol 10: 426–429.

45. SongS, HansonMJ, LiuBF, ChylackLT, LiangJJ (2008) Protein-protein interactions between lens vimentin and alphaB-crystallin using FRET acceptor photobleaching. Mol Vis 14: 1282–1287.

46. MollR, FrankeWW, SchillerDL, GeigerB, KreplerR (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31: 11–24.

47. YingW (2008) NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxidants & redox signaling 10: 179–206.

48. GeerBW, LindelDL, LindelDM (1979) Relationship of the oxidative pentose shunt pathway to lipid synthesis in Drosophila melanogaster. Biochem Genet 17: 881–895.

49. GeerBW, KrochkoD, WilliamsonJH (1979) Ontogeny, cell distribution, and the physiological role of NADP-malic enzyme in Drosophila melanogaster. Biochem Genet 17: 867–879.

50. MerrittTJ, KuczynskiC, SezginE, ZhuCT, KumagaiS, et al. (2009) Quantifying interactions within the NADP(H) enzyme network in Drosophila melanogaster. Genetics 182: 565–574.

51. ZhangH, RajasekaranNS, OroszA, XiaoX, RechsteinerM, et al. (2010) Selective degradation of aggregate-prone CryAB mutants by HSPB1 is mediated by ubiquitin-proteasome pathways. J Mol Cell Cardiol 49: 918–930.

52. RorthP (1998) Gal4 in the Drosophila female germline. Mech Dev 78: 113–118.

53. RubinGM, SpradlingAC (1982) Genetic transformation of Drosophila with transposable element vectors. Science 218: 348–353.

54. SpradlingAC, RubinGM (1982) Transposition of cloned P elements into Drosophila germ line chromosomes. Science 218: 341–347.

55. BischofJ, MaedaRK, HedigerM, KarchF, BaslerK (2006) An optimized transgenesis system for Drosophila using germ-line-specific φC31 integrases. PNAS 104: 3312–3317.

56. PotterCJ, LuoL (2010) Splinkerette PCR for Mapping Transposable Elements in Drosophila. PLoS ONE 5: e10168.

57. FreemanM (1996) Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87: 651–660.

58. DietzlG, ChenD, SchnorrerF, SuK-C, BarinovaY, et al. (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448: 151–156.

59. CarboneMA, AyrolesJF, YamamotoA, MorozovaTV, WestSA, et al. (2009) Overexpression of Myocilin in the Drosophila Eye Activates the Unfolded Protein Response: Implications for Glaucoma. PLoS ONE 4: e4216.

60. HanZ, OlsonEN (2005) Hand is a direct target of Tinman and GATA factors during Drosophila cardiogenesis and hematopoiesis. Development 132: 3525–3536.

61. OcorrKA, CrawleyT, GibsonG, BodmerR (2007) Genetic Variation for Cardiac Dysfunction in Drosophila. PLoS ONE 2: e601.

62. VoglerG, OcorrK (2009) Visualizing the Beating Heart in Drosophila. J Vis Exp 31: pii: 1425.

63. FinkM, Callol-MassotC, ChuA, Ruiz-LozanoP, BelmonteJCI, et al. (2009) A new method for detection and quantification of heartbeat parameters in Drosophila, zebrafish, and embryonic mouse hearts. BioTechniques 46: 101–113.

64. AlayariNN, VoglerG, Taghli-LamallemO, OcorrK, BodmerR, et al. (2009) Fluorescent Labeling of Drosophila Heart Structures. J Vis Exp e1423.

65. ScarbroughPM, MapuskarKA, MattsonDM, GiusD, WatsonWH, et al. (2012) Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress. Free Radical Biol Med 52: 436–43.

66. Miller A (1950) The Internal Anatomy and Histology of the Imago of Drosophila melanogaster. In: Demerec M, editor. Biology of Drosophila. New York: John Wiley and Sons, Inc. pp. 420–534.