Nebula/DSCR1 Upregulation Delays Neurodegeneration and Protects against APP-Induced Axonal Transport Defects by Restoring Calcineurin and GSK-3β Signaling

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Post-mortem brains from Down syndrome (DS) and Alzheimer's disease (AD) patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1), but its contribution to AD is not known. To gain insights into the role of DSCR1 in AD, we explored the functional interaction between DSCR1 and the amyloid precursor protein (APP), which is known to cause AD when duplicated or upregulated in DS. We find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression. Live-imaging reveals that Nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Furthermore, we show that Nebula upregulation protects against axonal transport defects by restoring calcineurin and GSK-3β signaling altered by APP overexpression, thereby preserving cargo-motor interactions. As impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, our findings imply that correcting calcineurin and GSK-3β signaling can prevent APP-induced pathologies. Our data further suggest that upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation and provides evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport impairments associated with AD.

Vyšlo v časopise: Nebula/DSCR1 Upregulation Delays Neurodegeneration and Protects against APP-Induced Axonal Transport Defects by Restoring Calcineurin and GSK-3β Signaling. PLoS Genet 9(9): e32767. doi:10.1371/journal.pgen.1003792
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003792

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1. WisniewskiKE, WisniewskiHM, WenGY (1985) Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 17: 278–282.

2. Epstein CJ (1995) Down syndrome (trisomy 21). In: Scriver CR B, AL, Sly WS, Vaile D, editor. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, Inc. pp. 749–794.

3. ReevesRH, BaxterLL, RichtsmeierJT (2001) Too much of a good thing: mechanisms of gene action in Down syndrome. Trends Genet 17: 83–88.

4. Rovelet-LecruxA, HannequinD, RauxG, Le MeurN, LaquerriereA, et al. (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38: 24–26.

5. SleegersK, BrouwersN, GijselinckI, TheunsJ, GoossensD, et al. (2006) APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 129: 2977–2983.

6. ErmakG, MorganTE, DaviesKJ (2001) Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. J Biol Chem 276: 38787–38794.

7. CookCN, HejnaMJ, MagnusonDJ, LeeJM (2005) Expression of calcipressin1, an inhibitor of the phosphatase calcineurin, is altered with aging and Alzheimer's disease. J Alzheimers Dis 8: 63–73.

8. SunX, WuY, ChenB, ZhangZ, ZhouW, et al. (2011) Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase-3 activation. J Biol Chem 286: 9049–9062.

9. ErmakG, HarrisCD, DaviesKJ (2002) The DSCR1 (Adapt78) isoform 1 protein calcipressin 1 inhibits calcineurin and protects against acute calcium-mediated stress damage, including transient oxidative stress. FASEB J 16: 814–824.

10. FuentesJJ, PritchardMA, PlanasAM, BoschA, FerrerI, et al. (1995) A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Mol Genet 4: 1935–1944.

11. FuentesJJ, GenescaL, KingsburyTJ, CunninghamKW, Perez-RibaM, et al. (2000) DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 9: 1681–1690.

12. GorlachJ, FoxDS, CutlerNS, CoxGM, PerfectJR, et al. (2000) Identification and characterization of a highly conserved calcineurin binding protein, CBP1/calcipressin, in Cryptococcus neoformans. EMBO J 19: 3618–3629.

13. KingsburyTJ, CunninghamKW (2000) A conserved family of calcineurin regulators. Genes Dev 14: 1595–1604.

14. RothermelB, VegaRB, YangJ, WuH, Bassel-DubyR, et al. (2000) A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J Biol Chem 275: 8719–8725.

15. ChangKT, ShiYJ, MinKT (2003) The Drosophila homolog of Down's syndrome critical region 1 gene regulates learning: implications for mental retardation. Proc Natl Acad Sci U S A 100: 15794–15799.

16. PortaS, SerraSA, HuchM, ValverdeMA, LlorensF, et al. (2007) RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration. Hum Mol Genet 16: 1039–1050.

17. SobradoM, RamirezBG, NeriaF, LizasoainI, ArbonesML, et al. (2012) Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury. J Neuroinflammation 9: 48.

18. WarrickJM, PaulsonHL, Gray-BoardGL, BuiQT, FischbeckKH, et al. (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93: 939–949.

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

20. SteffanJS, BodaiL, PallosJ, PoelmanM, McCampbellA, et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739–743.

21. JacksonGR, Wiedau-PazosM, SangTK, WagleN, BrownCA, et al. (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34: 509–519.

22. ChenHK, Fernandez-FunezP, AcevedoSF, LamYC, KaytorMD, et al. (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113: 457–468.

23. YangY, NishimuraI, ImaiY, TakahashiR, LuB (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37: 911–924.

24. IijimaK, LiuHP, ChiangAS, HearnSA, KonsolakiM, et al. (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease. Proc Natl Acad Sci U S A 101: 6623–6628.

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

26. MuhammadA, FloresI, ZhangH, YuR, StaniszewskiA, et al. (2008) Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation. Proc Natl Acad Sci U S A 105: 7327–7332.

27. Carmine-SimmenK, ProctorT, TschapeJ, PoeckB, TriphanT, et al. (2009) Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function. Neurobiol Dis 33: 274–281.

28. TorrojaL, ChuH, KotovskyI, WhiteK (1999) Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr Biol 9: 489–492.

29. GunawardenaS, GoldsteinLS (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32: 389–401.

30. StokinGB, LilloC, FalzoneTL, BruschRG, RockensteinE, et al. (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 307: 1282–1288.

31. SalehiA, DelcroixJD, BelichenkoPV, ZhanK, WuC, et al. (2006) Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51: 29–42.

32. StokinGB, GoldsteinLS (2006) Axonal transport and Alzheimer's disease. Annu Rev Biochem 75: 607–627.

33. MorfiniGA, BurnsM, BinderLI, KanaanNM, LaPointeN, et al. (2009) Axonal transport defects in neurodegenerative diseases. J Neurosci 29: 12776–12786.

34. KanaanNM, PiginoGF, BradyST, LazarovO, BinderLI, et al. (2013) Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system. Exp Neurol 246: 44–53.

35. GreeveI, KretzschmarD, TschapeJA, BeynA, BrellingerC, et al. (2004) Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. The Journal of neuroscience : the official journal of the Society for Neuroscience 24: 3899–3906.

36. BenzerS (1967) Behavioral mutants of Drosophila isolated by countercurrent distribution. Proc Natl Acad Sci USA 58: 1112–1119.

37. MuresanZ, MuresanV (2005) Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1. J Cell Biol 171: 615–625.

38. GroemerTW, ThielCS, HoltM, RiedelD, HuaY, et al. (2011) Amyloid precursor protein is trafficked and secreted via synaptic vesicles. PLoS One 6: e18754.

39. KohliBM, PfliegerD, MuellerLN, CarbonettiG, AebersoldR, et al. (2012) Interactome of the amyloid precursor protein APP in brain reveals a protein network involved in synaptic vesicle turnover and a close association with Synaptotagmin-1. J Proteome Res 11: 4075–4090.

40. LuoL, TullyT, WhiteK (1992) Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 9: 595–605.

41. TorrojaL, PackardM, GorczycaM, WhiteK, BudnikV (1999) The Drosophila beta-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. The Journal of neuroscience : the official journal of the Society for Neuroscience 19: 7793–7803.

42. AshleyJ, PackardM, AtamanB, BudnikV (2005) Fasciclin II signals new synapse formation through amyloid precursor protein and the scaffolding protein dX11/Mint. The Journal of neuroscience : the official journal of the Society for Neuroscience 25: 5943–5955.

43. SchusterCM, DavisGW, FetterRD, GoodmanCS (1996) Genetic dissection of structural and functional components of synaptic plasticity. I. Fasciclin II controls synaptic stabilization and growth. Neuron 17: 641–654.

44. SchusterCM, DavisGW, FetterRD, GoodmanCS (1996) Genetic dissection of structural and functional components of synaptic plasticity. II. Fasciclin II controls presynaptic structural plasticity. Neuron 17: 655–667.

45. MattsonMP, GleichmannM, ChengA (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60: 748–766.

46. Iijima-AndoK, HearnSA, ShentonC, GattA, ZhaoL, et al. (2009) Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. PLoS One 4: e8310.

47. Iijima-AndoK, SekiyaM, Maruko-OtakeA, OhtakeY, SuzukiE, et al. (2012) Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1. PLoS Genet 8: e1002918.

48. ShahpasandK, UemuraI, SaitoT, AsanoT, HataK, et al. (2012) Regulation of mitochondrial transport and inter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 32: 2430–2441.

49. PipernoG, FullerMT (1985) Monoclonal antibodies specific for an acetylated form of alpha-tubulin recognize the antigen in cilia and flagella from a variety of organisms. J Cell Biol 101: 2085–2094.

50. GodenaVK, RomanoG, RomanoM, AppocherC, KlimaR, et al. (2011) TDP-43 regulates Drosophila neuromuscular junctions growth by modulating Futsch/MAP1B levels and synaptic microtubules organization. PloS one 6: e17808.

51. WeaverC, LeidelC, SzpankowskiL, FarleyNM, ShubeitaGT, et al. (2013) Endogenous GSK-3/shaggy regulates bidirectional axonal transport of the amyloid precursor protein. Traffic 14: 295–308.

52. KleeCB, CrouchTH, KrinksMH (1979) Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci U S A 76: 6270–6273.

53. SouslovaEA, BelousovVV, LockJG, StrombladS, KasparovS, et al. (2007) Single fluorescent protein-based Ca2+ sensors with increased dynamic range. BMC Biotechnol 7: 37.

54. ChangKT, NiescierRF, MinKT (2011) Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons. Proc Natl Acad Sci U S A 108: 15456–15461.

55. HooperC, KillickR, LovestoneS (2008) The GSK3 hypothesis of Alzheimer's disease. Journal of neurochemistry 104: 1433–1439.

56. KimY, LeeYI, SeoM, KimSY, LeeJE, et al. (2009) Calcineurin dephosphorylates glycogen synthase kinase-3 beta at serine-9 in neuroblast-derived cells. J Neurochem 111: 344–354.

57. HernandezF, LucasJJ, AvilaJ (2012) GSK3 and Tau: Two Convergence Points in Alzheimer's Disease. J Alzheimers Dis 33 Suppl 1: S141–4.

58. Mondragon-RodriguezS, PerryG, ZhuX, MoreiraPI, WilliamsS (2012) Glycogen synthase kinase 3: a point of integration in Alzheimer's disease and a therapeutic target? Int J Alzheimers Dis 2012: 276803.

59. MorfiniG, SzebenyiG, ElluruR, RatnerN, BradyST (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 21: 281–293.

60. MudherA, ShepherdD, NewmanTA, MildrenP, JukesJP, et al. (2004) GSK-3beta inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9: 522–530.

61. SofolaO, KerrF, RogersI, KillickR, AugustinH, et al. (2010) Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease. PLoS Genet 6: e1001087.

62. LochheadPA, KinstrieR, SibbetG, RawjeeT, MorriceN, et al. (2006) A chaperone-dependent GSK3beta transitional intermediate mediates activation-loop autophosphorylation. Mol Cell 24: 627–633.

63. PeineauS, BradleyC, TaghibiglouC, DohertyA, BortolottoZA, et al. (2008) The role of GSK-3 in synaptic plasticity. Br J Pharmacol 153 Suppl 1: S428–437.

64. HughesK, NikolakakiE, PlyteSE, TottyNF, WoodgettJR (1993) Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 12: 803–808.

65. BhatRV, ShanleyJ, CorrellMP, FielesWE, KeithRA, et al. (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci U S A 97: 11074–11079.

66. PiginoG, MorfiniG, PelsmanA, MattsonMP, BradyST, et al. (2003) Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci 23: 4499–4508.

67. Pack-ChungE, KurshanPT, DickmanDK, SchwarzTL (2007) A Drosophila kinesin required for synaptic bouton formation and synaptic vesicle transport. Nat Neurosci 10: 980–989.

68. BarkusRV, KlyachkoO, HoriuchiD, DicksonBJ, SaxtonWM (2008) Identification of an axonal kinesin-3 motor for fast anterograde vesicle transport that facilitates retrograde transport of neuropeptides. Mol Biol Cell 19: 274–283.

69. HurdDD, SternM, SaxtonWM (1996) Mutation of the axonal transport motor kinesin enhances paralytic and suppresses Shaker in Drosophila. Genetics 142: 195–204.

70. GindhartJGJr, DesaiCJ, BeushausenS, ZinnK, GoldsteinLS (1998) Kinesin light chains are essential for axonal transport in Drosophila. J Cell Biol 141: 443–454.

71. ByrdDT, KawasakiM, WalcoffM, HisamotoN, MatsumotoK, et al. (2001) UNC-16, a JNK-signaling scaffold protein, regulates vesicle transport in C. elegans. Neuron 32: 787–800.

72. TodaH, MochizukiH, FloresR (2008) UNC-51/ATG1 kinase regulates axonal transport by mediating motor-cargo assembly. Genes Dev 22: 3292–3307.

73. HirokawaN, NodaY, TanakaY, NiwaS (2009) Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 10: 682–696.

74. RuelL, PantescoV, LutzY, SimpsonP, BourouisM (1993) Functional significance of a family of protein kinases encoded at the shaggy locus in Drosophila. EMBO J 12: 1657–1669.

75. TakeoS, SwansonSK, NandananK, NakaiY, AigakiT, et al. (2012) Shaggy/glycogen synthase kinase 3beta and phosphorylation of Sarah/regulator of calcineurin are essential for completion of Drosophila female meiosis. Proc Natl Acad Sci U S A 109: 6382–6389.

76. MitchellCS, LeeRH (2012) Cargo distributions differentiate pathological axonal transport impairments. J Theor Biol 300: 277–291.

77. ChangKT, MinKT (2005) Drosophila melanogaster homolog of Down syndrome critical region 1 is critical for mitochondrial function. Nat Neurosci 8: 1577–1585.

78. LaFerlaFM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat Rev Neurosci 3: 862–872.

79. ReeseLC, TaglialatelaG (2011) A role for calcineurin in Alzheimer's disease. Curr Neuropharmacol 9: 685–692.

80. GarwoodC, FaizullabhoyA, WhartonSB, IncePG, HeathP, et al. (2013) Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol [epub ahead of print doi:10.1111/nan.12033

81. D'AmelioM, CavallucciV, MiddeiS, MarchettiC, PacioniS, et al. (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat Neurosci 14: 69–76.

82. SantosSF, PierrotN, MorelN, GaillyP, SindicC, et al. (2009) Expression of human amyloid precursor protein in rat cortical neurons inhibits calcium oscillations. The Journal of neuroscience : the official journal of the Society for Neuroscience 29: 4708–4718.

83. ChenS, OwensGC, CrossinKL, EdelmanDB (2007) Serotonin stimulates mitochondrial transport in hippocampal neurons. Mol Cell Neurosci 36: 472–483.

84. MorelM, AutheletM, DedeckerR, BrionJP (2010) Glycogen synthase kinase-3beta and the p25 activator of cyclin dependent kinase 5 increase pausing of mitochondria in neurons. Neuroscience 167: 1044–1056.

85. BradyST, PfisterKK, BloomGS (1990) A monoclonal antibody against kinesin inhibits both anterograde and retrograde fast axonal transport in squid axoplasm. Proc Natl Acad Sci U S A 87: 1061–1065.

86. PillingAD, HoriuchiD, LivelyCM, SaxtonWM (2006) Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol Biol Cell 17: 2057–2068.

87. ReisGF, YangG, SzpankowskiL, WeaverC, ShahSB, et al. (2012) Molecular motor function in axonal transport in vivo probed by genetic and computational analysis in Drosophila. Mol Biol Cell 23: 1700–1714.

88. GunawardenaS, YangG, GoldsteinLS (2013) Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo. Hum Mol Genet [Epub ahead of print].

89. De VosK, SeverinF, Van HerrewegheF, VancompernolleK, GoossensV, et al. (2000) Tumor necrosis factor induces hyperphosphorylation of kinesin light chain and inhibits kinesin-mediated transport of mitochondria. J Cell Biol 149: 1207–1214.

90. MorelM, HeraudC, NicaiseC, SuainV, BrionJP (2012) Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer's disease: implications for axoplasmic transport. Acta neuropathologica 123: 71–84.

91. AnderssonME, SjolanderA, AndreasenN, MinthonL, HanssonO, et al. (2007) Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease. International journal of molecular medicine 20: 233–239.

92. DierssenM, ArqueG, McDonaldJ, AndreuN, Martinez-CueC, et al. (2011) Behavioral characterization of a mouse model overexpressing DSCR1/RCAN1. PLoS One 6: e17010.

93. CostaAC (2012) Alzheimer disease: Treatment of Alzheimer disease in Down syndrome. Nature reviews Neurology 8: 182–184.

94. SullivanKM, RubinGM (2002) The Ca(2+)-calmodulin-activated protein phosphatase calcineurin negatively regulates EGF receptor signaling in Drosophila development. Genetics 161: 183–193.

95. MontellC, JonesK, HafenE, RubinG (1985) Rescue of the Drosophila phototransduction mutation trp by germline transformation. Science 230: 1040–1043.

96. KuznickiML, GunawardenaS (2010) In vivo visualization of synaptic vesicles within Drosophila larval segmental axons. J Vis Exp (44) pii: 2151.

97. LouieK, RussoGJ, SalkoffDB, WellingtonA, ZinsmaierKE (2008) Effects of imaging conditions on mitochondrial transport and length in larval motor axons of Drosophila. Comp Biochem Physiol A Mol Integr Physiol 151: 159–172.

98. ChangKT, MinKT (2009) Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome. Proc Natl Acad Sci U S A 106: 17117–17122.