#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

DJ-1 Decreases Neural Sensitivity to Stress by Negatively Regulating Daxx-Like Protein through dFOXO


DJ-1, a Parkinson's disease (PD)–associated gene, has been shown to protect against oxidative stress in Drosophila. However, the molecular mechanism underlying oxidative stress-induced phenotypes, including apoptosis, locomotive defects, and lethality, in DJ-1-deficient flies is not fully understood. Here we showed that Daxx-like protein (DLP), a Drosophila homologue of the mammalian Death domain-associated protein (Daxx), was upregulated under oxidative stress conditions in the loss-of-function mutants of Drosophila DJ-1β, a Drosophila homologue of DJ-1. DLP overexpression induced apoptosis via the c-Jun N-terminal kinase (JNK)/Drosophila forkhead box subgroup O (dFOXO) pathway, whereas loss of DLP increased resistance to oxidative stress and UV irradiation. Moreover, the oxidative stress-induced phenotypes of DJ-1β mutants were dramatically rescued by DLP deficiency, suggesting that enhanced expression of DLP contributes to the DJ-1β mutant phenotypes. Interestingly, we found that dFOXO was required for the increase in DLP expression in DJ-1β mutants and that dFOXO activity was increased in the heads of DJ-1β mutants. In addition, subcellular localization of DLP appeared to be influenced by DJ-1 expression so that cytosolic DLP was increased in DJ-1β mutants. Similarly, in mammalian cells, Daxx translocation from the nucleus to the cytosol was suppressed by overexpressed DJ-1β under oxidative stress conditions; and, furthermore, targeted expression of DJ-1β to mitochondria efficiently inhibited the Daxx translocation. Taken together, our findings demonstrate that DJ-1β protects flies against oxidative stress- and UV-induced apoptosis by regulating the subcellular localization and gene expression of DLP, thus implying that Daxx-induced apoptosis is involved in the pathogenesis of DJ-1-associated PD.


Vyšlo v časopise: DJ-1 Decreases Neural Sensitivity to Stress by Negatively Regulating Daxx-Like Protein through dFOXO. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003412
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003412

Souhrn

DJ-1, a Parkinson's disease (PD)–associated gene, has been shown to protect against oxidative stress in Drosophila. However, the molecular mechanism underlying oxidative stress-induced phenotypes, including apoptosis, locomotive defects, and lethality, in DJ-1-deficient flies is not fully understood. Here we showed that Daxx-like protein (DLP), a Drosophila homologue of the mammalian Death domain-associated protein (Daxx), was upregulated under oxidative stress conditions in the loss-of-function mutants of Drosophila DJ-1β, a Drosophila homologue of DJ-1. DLP overexpression induced apoptosis via the c-Jun N-terminal kinase (JNK)/Drosophila forkhead box subgroup O (dFOXO) pathway, whereas loss of DLP increased resistance to oxidative stress and UV irradiation. Moreover, the oxidative stress-induced phenotypes of DJ-1β mutants were dramatically rescued by DLP deficiency, suggesting that enhanced expression of DLP contributes to the DJ-1β mutant phenotypes. Interestingly, we found that dFOXO was required for the increase in DLP expression in DJ-1β mutants and that dFOXO activity was increased in the heads of DJ-1β mutants. In addition, subcellular localization of DLP appeared to be influenced by DJ-1 expression so that cytosolic DLP was increased in DJ-1β mutants. Similarly, in mammalian cells, Daxx translocation from the nucleus to the cytosol was suppressed by overexpressed DJ-1β under oxidative stress conditions; and, furthermore, targeted expression of DJ-1β to mitochondria efficiently inhibited the Daxx translocation. Taken together, our findings demonstrate that DJ-1β protects flies against oxidative stress- and UV-induced apoptosis by regulating the subcellular localization and gene expression of DLP, thus implying that Daxx-induced apoptosis is involved in the pathogenesis of DJ-1-associated PD.


Zdroje

1. EmeritJ, EdeasM, BricaireF (2004) Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 58: 39–46.

2. LinMT, BealMF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787–795.

3. TsangAHK, ChungKKK (2009) Oxidative and nitrosative stress in Parkinson's disease. Biochim Biophys Acta 1792: 643–650.

4. JennerP (2007) Oxidative stress and Parkinson's disease. Handb Clin Neurol 83: 507–520.

5. ZhouC, HuangY, PrzedborskiS (2008) Oxidative Stress in Parkinson's Disease. Ann N Y Acad Sci 1147: 93–104.

6. JennerP (2003) Oxidative stress in Parkinson's disease. Ann Neurol 53: S26–S38.

7. GiassonBI, LeeVMY (2000) A new link between pesticides and Parkinson's disease. Nat Neurosci 3: 1227–1228.

8. ChungKKK, ThomasB, LiX, PletnikovaO, TroncosoJC, et al. (2004) S-nitrosylation of parkin regulates ubiquitination and compromises Parkin's protective function. Science 304: 1328–1331.

9. LaVoieMJ, OstaszewskiBL, WeihofenA, SchlossmacherMG, SelkoeDJ (2005) Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11: 1214–1221.

10. PesahY, PhamT, BurgessH, MiddlebrooksB, VerstrekenP, et al. (2004) Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131: 2183–2194.

11. MenziesFM, YenisettiSC, MinK-T (2005) Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Curr Biol 15: 1578–1582.

12. MeulenerM, WhitworthAJ, Armstrong-GoldCE, RizzuP, HeutinkP, et al. (2005) Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease. Curr Biol 15: 1572–1577.

13. ClarkIE, DodsonMW, JiangC, CaoJH, HuhJR, et al. (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441: 1162–1166.

14. Andres-MateosE, PerierC, ZhangL, Blanchard-FillionB, GrecoTM, et al. (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A 104: 14807–14812.

15. GautierCA, KitadaT, ShenJ (2008) Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A 105: 11364–11369.

16. WangD, TangB, ZhaoG, PanQ, XiaK, et al. (2008) Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons. Mol Neurodegener 3: 1–7.

17. LevyO, MalageladaC, GreeneL (2009) Cell death pathways in Parkinson's disease: proximal triggers, distal effectors, and final steps. Apoptosis 14: 478–500.

18. NagakuboD, TairaT, KitauraH, IkedaM, TamaiK, et al. (1997) DJ-1, a novel oncogene which transforms Mouse NIH3T3 cells in cooperation withras. Biochem Biophys Res Commun 231: 509–513.

19. KimRH, PetersM, JangY, ShiW, PintilieM, et al. (2005) DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7: 263–273.

20. PardoM, GarcíaÁ, ThomasB, PiñeiroA, AkoulitchevA, et al. (2006) The characterization of the invasion phenotype of uveal melanoma tumour cells shows the presence of MUC18 and HMG-1 metastasis markers and leads to the identification of DJ-1 as a potential serum biomarker. Int J Cancer 119: 1014–1022.

21. TianM, CuiY-Z, SongG-H, ZongM-J, ZhouX-Y, et al. (2008) Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients. BMC Cancer 8: 1–11.

22. BonifatiV, RizzuP, SquitieriF, KriegerE, VanacoreN, et al. (2003) DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 24: 159–160.

23. KahlePJ, WaakJ, GasserT (2009) DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders. Free Radic Biol Med 47: 1354–1361.

24. ParkJ, KimSY, ChaG-H, LeeSB, KimS, et al. (2005) Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction. Gene 361: 133–139.

25. KimRH, SmithPD, AleyasinH, HayleyS, MountMP, et al. (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A 102: 5215–5220.

26. BretaudS, AllenC, InghamPW, BandmannO (2007) p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease. J Neurochem 00: 1626–1635.

27. LiuF, NguyenJL, HullemanJD, LiL, RochetJ-C (2008) Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson's disease. J Neurochem 105: 2435–2453.

28. ZhouW, FreedCR (2005) DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T α-synuclein toxicity. J Biol Chem 280: 43150–43158.

29. ClementsCM, McNallyRS, ContiBJ, MakTW, TingJP-Y (2006) DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci U S A 103: 15091–15096.

30. ZhongN, XuJ (2008) Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1α: regulation by SUMOylation and oxidation. Hum Mol Genet 17: 3357–3367.

31. ImJ-Y, LeeK-W, WooJ-M, JunnE, MouradianMM (2012) DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum Mol Genet 21: 3013–3024.

32. MoJS, KimMY, AnnEJ, HongJA, ParkHS (2008) DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death. Cell Death Differ 15: 1030–1041.

33. JunnE, TaniguchiH, JeongBS, ZhaoX, IchijoH, et al. (2005) Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci U S A 102: 9691–9696.

34. FanJ, RenH, JiaN, FeiE, ZhouT, et al. (2008) DJ-1 decreases Bax expression through repressing p53 transcriptional acctivity. J Biol Chem 283: 4022–4030.

35. YangX, Khosravi-FarR, ChangHY, BaltimoreD (1997) Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 89: 1067–1076.

36. ToriiS, EganDA, EvansRA, ReedJC (1999) Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). EMBO J 18: 6037–6049.

37. WajantH (2002) The Fas Signaling Pathway: More Than a Paradigm. Science 296: 1635–1636.

38. SalomoniP, KhelifiAF (2006) Daxx: death or survival protein? Trends Cell Biol 16: 97–104.

39. ChangHY, NishitohH, YangX, IchijoH, BaltimoreD (1998) Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science 281: 1860–1863.

40. KhelifiAF, D'AlcontresMS, SalomoniP (2005) Daxx is required for stress-induced cell death and JNK activation. Cell Death Differ 12: 724–733.

41. KimKS, HwangH-A, ChaeS-K, HaH, KwonK-S (2005) Upregulation of Daxx mediates apoptosis in response to oxidative stress. J Cell Biochem 96: 330–338.

42. RaoulC, BarthelemyC, CouzinetA, HancockD, PettmannB, et al. (2005) Expression of a dominant negative form of Daxx in vivo rescues motoneurons from Fas (CD95)-induced cell death. J Neurobiol 62: 178–188.

43. RaoulC, EstévezAG, NishimuneH, ClevelandDW, deLapeyrièreO, et al. (2002) Motoneuron death triggered by a specific pathway downstream of Fas: Potentiation by ALS-linked SOD1 mutations. Neuron 35: 1067–1083.

44. KarunakaranS, DiwakarL, SaeedU, AgarwalV, RamakrishnanS, et al. (2007) Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson's disease: protection by α-lipoic acid. FASEB J 21: 2226–2236.

45. BodaiL, PardiN, ÚjfaludiZ, BereczkiO, KomonyiO, et al. (2007) Daxx-like protein of Drosophila interacts with Dmp53 and affects longevity and Ark mRNA level. J Biol Chem 282: 36386–36393.

46. WaakJ, WeberSS, GörnerK, SchallC, IchijoH, et al. (2009) Oxidizable residues mediating protein stability and cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1. J Biol Chem 284: 14245–14257.

47. EssersMA, WeijzenS, de Vries-SmitsAM, SaarloosI, de RuiterND, et al. (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23: 4802–4812.

48. LuoX, PuigO, HyunJ, BohmannD, JasperH (2007) Foxo and Fos regulate the decision between cell death and survival in response to UV irradiation. EMBO J 26: 380–390.

49. YangY, GehrkeS, HaqueME, ImaiY, KosekJ, et al. (2005) Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci U S A 102: 13670–13675.

50. AleyasinH, RousseauxMWC, MarcogliesePC, HewittSJ, IrrcherI, et al. (2010) DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway. Proc Natl Acad Sci U S A 107: 3186–3191.

51. BiggsWH3rd, CaveneeWK, ArdenKC (2001) Identification and characterization of members of the FKHR (FOXO) subclass of winged-helix transcription factors in the mouse. Mamm Genome 12: 416–425.

52. Lavara-CulebrasE, Muñoz-SorianoV, Gómez-PastorR, MatallanaE, ParicioN (2010) Effects of pharmacological agents on the lifespan phenotype of Drosophila DJ-1β mutants. Gene 462: 26–33.

53. ParkJ, LeeSB, LeeS, KimY, SongS, et al. (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441: 1157–1161.

54. KohH, ChungJ (2012) PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity. Mol Cells 34: 7–13.

55. FahnS, CohenG (1992) The oxidant stress hypothesis in Parkinson's disease: Evidence supporting it. Ann Neurol 32: 804–812.

56. JennerP, OlanowCW (1996) Oxidative stress and the pathogenesis of Parkinson's disease. Neurology 47: 161S–170S.

57. HaldA, LothariusJ (2005) Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp Neurol 193: 279–290.

58. BrunetA, BonniA, ZigmondMJ, LinMZ, JuoP, et al. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.

59. SongJJ, LeeYJ (2003) Catalase, but not MnSOD, inhibits glucose deprivation-activated ASK1-MEK-MAPK signal transduction pathway and prevents relocalization of Daxx: Hydrogen peroxide as a major second messenger of metabolic oxidative stress. J Cell Biochem 90: 304–314.

60. CharetteSJ, LavoieJN, LambertH, LandryJ (2000) Inhibition of Daxx-mediated apoptosis by Heat Shock Protein 27. Mol Cell Biol 20: 7602–7612.

61. LeeJH, LeeE, ParkJ, KimE, KimJ, et al. (2003) In vivo p53 function is indispensable for DNA damage-induced apoptotic signaling in Drosophila. FEBS Lett 550: 5–10.

62. SonJH, ChunHS, JohTH, ChoS, ContiB, et al. (1999) Neuroprotection and neuronal differentiation studies using substantia nigra dopaminergic cells derived from transgenic Mouse embryos. J Neurosci 19: 10–20.

63. LeeNG, HongYK, YuSY, HanSY, GeumD, et al. (2007) dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun-N-terminal kinase activation. FEBS Lett 581: 2625–2632.

64. FeanyMB, BenderWW (2000) A Drosophila model of Parkinson's disease. Nature 404: 394–398.

65. HongYK, LeeNG, LeeMJ, ParkMS, ChoiG, et al. (2009) dXNP/DATRX increases apoptosis via the JNK and dFOXO pathway in Drosophila neurons. Biochem Biophys Res Commun 384: 160–166.

66. YangJS, NamHJ, SeoM, HanSK, ChoiY, et al. (2011) OASIS: Online application for the survival analysis of lifespan assays performed in aging research. PLoS ONE 6: e23525 doi:10.1371/journal.pone.0023525.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2013 Číslo 4
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#