Regulation of Synaptic /Neuroligin Abundance by the /Nrf Stress Response Pathway Protects against Oxidative Stress

English version České info

The Nrf family of transcription factors mediates adaptive responses to stress and longevity, but the identities of the crucial Nrf targets, and the tissues in which they function in multicellular organisms to promote survival, are not known. Here, we use whole transcriptome RNA sequencing to identify 810 genes whose expression is controlled by the SKN-1/Nrf2 negative regulator WDR-23 in the nervous system of Caenorhabditis elegans. Among the genes identified is the synaptic cell adhesion molecule nlg-1/neuroligin. We find that the synaptic abundance of NLG-1 protein increases following pharmacological treatments that generate oxidative stress or by the genetic activation of skn-1. Increasing nlg-1 dosage correlates with increased survival in response to oxidative stress, whereas genetic inactivation of nlg-1 reduces survival and impairs skn-1-mediated stress resistance. We identify a canonical SKN-1 binding site in the nlg-1 promoter that binds to SKN-1 in vitro and is necessary for SKN-1 and toxin-mediated increases in nlg-1 expression in vivo. Together, our results suggest that SKN-1 activation in the nervous system can confer protection to organisms in response to stress by directly regulating nlg-1/neuroligin expression.

Vyšlo v časopise: Regulation of Synaptic /Neuroligin Abundance by the /Nrf Stress Response Pathway Protects against Oxidative Stress. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004100
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004100

Souhrn

Zdroje

1. FinkelT, HolbrookNJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408 : 239–247.

2. HalliwellB (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97 : 1634–1658.

3. Abou-SleimanPM, MuqitMM, WoodNW (2006) Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7 : 207–219.

4. ZanaM, JankaZ, KalmanJ (2007) Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease. Neurobiol Aging 28 : 648–676.

5. ItohK, ChibaT, TakahashiS, IshiiT, IgarashiK, et al. (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236 : 313–322.

6. KobayashiM, YamamotoM (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 46 : 113–140.

7. SykiotisGP, BohmannD (2010) Stress-activated cap'n'collar transcription factors in aging and human disease. Sci Signal 3: re3.

8. LeeJM, LiJ, JohnsonDA, SteinTD, KraftAD, et al. (2005) Nrf2, a multi-organ protector? FASEB J 19 : 1061–1066.

9. ItohK, WakabayashiN, KatohY, IshiiT, IgarashiK, et al. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13 : 76–86.

10. KraftAD, JohnsonDA, JohnsonJA (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J Neurosci 24 : 1101–1112.

11. LeeJM, ShihAY, MurphyTH, JohnsonJA (2003) NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J Biol Chem 278 : 37948–37956.

12. LeeJM, CalkinsMJ, ChanK, KanYW, JohnsonJA (2003) Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 278 : 12029–12038.

13. AnJH, BlackwellTK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17 : 1882–1893.

14. BishopNA, GuarenteL (2007) Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447 : 545–549.

15. VanduynN, SettivariR, WongG, NassR (2010) SKN-1/Nrf2 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of methylmercury toxicity. Toxicol Sci 118 : 613–624.

16. SettivariR, VanduynN, LevoraJ, NassR (2013) The Nrf2/SKN-1-dependent glutathione S-transferase pi homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism. Neurotoxicology 38C: 51–60.

17. VanDuynN, SettivariR, LeVoraJ, ZhouS, UnrineJ, et al. (2013) The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration. J Neurochem 124 : 147–157.

18. BenedettoA, AuC, AvilaDS, MilatovicD, AschnerM (2010) Extracellular dopamine potentiates mn-induced oxidative stress, lifespan reduction, and dopaminergic neurodegeneration in a BLI-3-dependent manner in Caenorhabditis elegans. PLoS Genet 6: e1001084.

19. ChoeKP, PrzybyszAJ, StrangeK (2009) The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans. Mol Cell Biol 29 : 2704–2715.

20. StaabTA, GriffenTC, CorcoranC, EvgrafovO, KnowlesJA, et al. (2013) The Conserved SKN-1/Nrf2 Stress Response Pathway Regulates Synaptic Function in Caenorhabditis elegans. PLoS Genet 9: e1003354.

21. HasegawaK, MiwaJ (2010) Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. PloS one 5: e11194.

22. wormbase.org Wormbase web site. Release ws236 ed.

23. BlumenthalT (2012) Trans-splicing and operons in C. elegans. WormBook 1–11.

24. MelendezA, TalloczyZ, SeamanM, EskelinenEL, HallDH, et al. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301 : 1387–1391.

25. Takacs-VellaiK, VellaiT, PuotiA, PassannanteM, WickyC, et al. (2005) Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans. Curr Biol 15 : 1513–1517.

26. HallDH, HedgecockEM (1991) Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell 65 : 837–847.

27. LabrousseAM, ZappaterraMD, RubeDA, van der BliekAM (1999) C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4 : 815–826.

28. DennisGJr, ShermanBT, HosackDA, YangJ, GaoW, et al. (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4: P3.

29. IwasakiK, ToyonagaR (2000) The Rab3 GDP/GTP exchange factor homolog AEX-3 has a dual function in synaptic transmission. EMBO J 19 : 4806–4816.

30. HunterJW, MullenGP, McManusJR, HeatherlyJM, DukeA, et al. (2010) Neuroligin-deficient mutants of C. elegans have sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity. Dis Model Mech 3 : 366–376.

31. KohnRE, DuerrJS, McManusJR, DukeA, RakowTL, et al. (2000) Expression of multiple UNC-13 proteins in the Caenorhabditis elegans nervous system. Mol Biol Cell 11 : 3441–3452.

32. CharlieNK, ThomureAM, SchadeMA, MillerKG (2006) The Dunce cAMP phosphodiesterase PDE-4 negatively regulates G alpha(s)-dependent and G alpha(s)-independent cAMP pools in the Caenorhabditis elegans synaptic signaling network. Genetics 173 : 111–130.

33. Thomas-ChollierM, SandO, TuratsinzeJV, JankyR, DefranceM, et al. (2008) RSAT: regulatory sequence analysis tools. Nucleic Acids Res 36: W119–127.

34. NiuW, LuZJ, ZhongM, SarovM, MurrayJI, et al. (2011) Diverse transcription factor binding features revealed by genome-wide ChIP-seq in C. elegans. Genome Res 21 : 245–254.

35. HuZ, HomS, KudzeT, TongXJ, ChoiS, et al. (2012) Neurexin and neuroligin mediate retrograde synaptic inhibition in C. elegans. Science 337 : 980–984.

36. CalahorroF, AlejandreE, Ruiz-RubioM (2009) Osmotic avoidance in Caenorhabditis elegans: synaptic function of two genes, orthologues of human NRXN1 and NLGN1, as candidates for autism. J Vis Exp (34) 1616.

37. FeinbergEH, VanhovenMK, BendeskyA, WangG, FetterRD, et al. (2008) GFP Reconstitution Across Synaptic Partners (GRASP) defines cell contacts and synapses in living nervous systems. Neuron 57 : 353–363.

38. PaekJ, LoJY, NarasimhanSD, NguyenTN, Glover-CutterK, et al. (2012) Mitochondrial SKN-1/Nrf Mediates a Conserved Starvation Response. Cell Metab 16 : 526–537.

39. BlackwellTK, BowermanB, PriessJR, WeintraubH (1994) Formation of a monomeric DNA binding domain by Skn-1 bZIP and homeodomain elements. Science 266 : 621–628.

40. SieburthD, MadisonJM, KaplanJM (2007) PKC-1 regulates secretion of neuropeptides. Nat Neurosci 10 : 49–57.

41. DittmanJS, KaplanJM (2006) Factors regulating the abundance and localization of synaptobrevin in the plasma membrane. Proc Natl Acad Sci U S A 103 : 11399–11404.

42. OliveiraRP, Porter AbateJ, DilksK, LandisJ, AshrafJ, et al. (2009) Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf. Aging Cell 8 : 524–541.

43. PrzybyszAJ, ChoeKP, RobertsLJ, StrangeK (2009) Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone. Mech Ageing Dev 130 : 357–369.

44. TulletJM, HertweckM, AnJH, BakerJ, HwangJY, et al. (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132 : 1025–1038.

45. InoueH, HisamotoN, AnJH, OliveiraRP, NishidaE, et al. (2005) The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response. Genes Dev 19 : 2278–2283.

46. ZubovychIO, StraudS, RothMG (2010) Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans. Mol Biol Cell 21 : 956–969.

47. NarendraD, TanakaA, SuenDF, YouleRJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183 : 795–803.

48. YouleRJ, van der BliekAM (2012) Mitochondrial fission, fusion, and stress. Science 337 : 1062–1065.

49. ParkSK, TedescoPM, JohnsonTE (2009) Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1. Aging cell 8 : 258–269.

50. LuoL, O'LearyDD (2005) Axon retraction and degeneration in development and disease. Annual review of neuroscience 28 : 127–156.

51. FengZ, LiL, NgPY, PorterAG (2002) Neuronal differentiation and protection from nitric oxide-induced apoptosis require c-Jun-dependent expression of NCAM140. Mol Cell Biol 22 : 5357–5366.

52. KlementievB, NovikovaT, KorshunovaI, BerezinV, BockE (2008) The NCAM-derived P2 peptide facilitates recovery of cognitive and motor function and ameliorates neuropathology following traumatic brain injury. Eur J Neurosci 27 : 2885–2896.

53. ScapagniniG, VastoS, AbrahamNG, CarusoC, ZellaD, et al. (2011) Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Molecular neurobiology 44 : 192–201.

54. ChakrabortyS, AschnerM (2012) Altered manganese homeostasis: implications for BLI-3-dependent dopaminergic neurodegeneration and SKN-1 protection in C. elegans. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements 26 : 183–187.

55. JoshiG, JohnsonJA (2012) The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent patents on CNS drug discovery 7 : 218–229.

56. BertholetAM, MilletAM, GuillerminO, DaloyauM, DavezacN, et al. (2013) OPA1 loss of function affects in vitro neuronal maturation. Brain : a journal of neurology 136 : 1518–1533.

57. DurieuxJ, WolffS, DillinA (2011) The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144 : 79–91.

58. SudhofTC (2008) Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455 : 903–911.

59. BottosA, RissoneA, BussolinoF, AreseM (2011) Neurexins and neuroligins: synapses look out of the nervous system. Cell Mol Life Sci 68 : 2655–2666.

60. ZhangC, MilunskyJM, NewtonS, KoJ, ZhaoG, et al. (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci 29 : 10843–10854.

61. ComolettiD, De JacoA, JenningsLL, FlynnRE, GaiettaG, et al. (2004) The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci 24 : 4889–4893.

62. ChihB, EngelmanH, ScheiffeleP (2005) Control of excitatory and inhibitory synapse formation by neuroligins. Science 307 : 1324–1328.

63. GhezzoA, ViscontiP, AbruzzoPM, BolottaA, FerreriC, et al. (2013) Oxidative Stress and Erythrocyte Membrane Alterations in Children with Autism: Correlation with Clinical Features. PLoS One 8: e66418.

64. GorrindoP, LaneCJ, LeeEB, McLaughlinB, LevittP (2013) Enrichment of elevated plasma F2t-isoprostane levels in individuals with autism who are stratified by presence of gastrointestinal dysfunction. PLoS One 8: e68444.

65. RossignolDA, FryeRE (2012) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 17 : 290–314.

66. MelloCC, KramerJM, StinchcombD, AmbrosV (1991) Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J 10 : 3959–3970.

67. Ch'ngQ, SieburthD, KaplanJM (2008) Profiling synaptic proteins identifies regulators of insulin secretion and lifespan. PLoS Genet 4: e1000283.

68. TrapnellC, WilliamsBA, PerteaG, MortazaviA, KwanG, et al. (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28 : 511–515.