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A central role for calcineurin in protein misfolding neurodegenerative diseases

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Abstract

Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegenerative diseases affecting humans and animals. Dysregulation of calcium (Ca2+) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca2+ in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca2+ storing organelle, ultimately leading to neuronal dysfunction and apoptosis. Calcineurin (CaN), a Ca2+/calmodulin-dependent serine/threonine phosphatase, has been implicated in T cells activation through the induction of nuclear factor of activated T cells (NFAT). In addition to the involvement of several other signaling cascades, CaN has been shown to play a role in early synaptic dysfunction and neuronal death. Therefore, inhibiting hyperactivated CaN in early stages of disease might be a promising therapeutic strategy for treating patients with protein misfolding diseases. In this review, we briefly summarize the structure of CaN, inhibition mechanisms by which immunosuppressants inhibit CaN, role of CaN in maintaining neuronal and synaptic integrity and homeostasis and the role played by CaN in protein unfolding/misfolding neurodegenerative diseases.

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Abbreviations

FAT:

Fast axonal transport

ER:

Endoplasmic reticulum

CaN:

Calcineurin

NFAT:

Nuclear factor of activated T cells

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

ALS:

Amyotrophic lateral sclerosis

FTD:

Frontotemporal dementia

HD:

Huntington’s disease

CJD:

Creutzfeldt-Jacob disease

BAD:

Bcl2-associated death promoter

CREB:

cAMP response element-binding

SERCA:

Sarcoplasmic endoplasmic reticulum Calcium adenosine

CaM:

Calmodulin

IP3R:

Inositol 1,4,5-triphosphate receptors

RyR:

Ryanodine receptors

TFEB:

Transcription factor EB

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

BDNF:

Brain-derived neuronal growth factor

UPR:

Unfolded protein response

GluA1:

Glutamine A1

GluA2:

Glutamine A2

trkB:

Tropomyosin-related kinase B

Aβ:

Amyloid beta

MEF2:

Myocyte enhancer factor 2

References

  1. Soto C (2003) Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4:49–60

    Article  CAS  PubMed  Google Scholar 

  2. Mukherjee A, Soto C (2011) Role of calcineurin in neurodegeneration produced by misfolded proteins and endoplasmic reticulum stress. Curr Opin Cell Biol 23:223–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shah SZA, Zhao D, Khan SH, Yang L (2015) Unfolded response pathways in neurodegenerative diseases. J Mol Neurosci 57(4):529–537

    Article  CAS  PubMed  Google Scholar 

  4. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366

    Article  CAS  PubMed  Google Scholar 

  5. Beriault DR, Werstuck GH (1833) Detection and quantification of endoplasmic reticulum stress in living cells using the fluorescent compound, Thioflavin T. Biochimica et Biophysica Acta 2013:2293–2301

    Google Scholar 

  6. Dineley KT, Kayed R, Neugebauer V, Fu Y, Zhang W, Reese LC, Taglialatela G (2010) Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice. J Neurosci Res 88(2923–2932):70

    Google Scholar 

  7. Mukherjee A, Morales-Scheihing D, Gonzalez-Romero D, Green K, Taglialatela G, Soto C (2010) Calcineurin inhibition at the clinical phase of prion disease reduces neurodegeneration, improves behavioral alterations and increases animal survival. PLoS Pathog 6(10):e1001138

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Hudry E, Wu HY, Arbel-Ornath M, Hashimoto T, Matsouaka R, Fan Z, Spires-Jones TL, Betensky RA, Bacskai BJ, Hyman BT (2012) Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer’s disease. J Neurosci 32:3176–3192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cavallucci V, Berretta N, Nobili A, Nisticò R, Mercuri NB, D’Amelio M (2013) Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer’s disease. Neuromol Med 15:541–548

    Article  CAS  Google Scholar 

  10. Shah SZA, Zhao D, Khan SH, Yang L (2015) Regulatory mechanisms of endoplasmic reticulum resident IP3 receptors. J Mol Neurosci 56(4):938–948

    Article  CAS  PubMed  Google Scholar 

  11. Goto S, Matsukado Y, Mihara Y, Inoue N, Miyamoto E (1986) The distribution of calcineurin in rat brain by light and electron microscopic immunohistochemistry and enzyme-immunoassay. Brain Res 397:161–172

    Article  CAS  PubMed  Google Scholar 

  12. Goto S, Matsukado Y, Mihara Y, Inoue N, Miyamoto E (1986) Calcineurin in human brain and its relation to extrapyramidal system. Immunohistochemical study on postmortem human brains. Acta Neuropathol 72:150–156

    Article  CAS  PubMed  Google Scholar 

  13. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC (1999) Ca2+ induced apoptosis through calcineurin dephosphorylation of BAD. Science 284:339–343

    Article  CAS  PubMed  Google Scholar 

  14. Groth RD, Dunbar RL, Mermelstein PG (2003) Calcineurin regulation of neuronal plasticity. Biochem Biophys Res Commun 311:1159–1171

    Article  CAS  PubMed  Google Scholar 

  15. Gan KJ, Silverman MA (2015) Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer-treated hippocampal neurons. Mol Biol Cell 26:1058–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pineda JR, Pardo R, Zala D, Yu H, Humbert S, Saudou F (2009) Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington’s disease. Mol Brain 2:33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Lehotsky J, Kaplan P, Babusikova E, Strapkova A, Murin R (2003) Molecular pathways of endoplasmic reticulum dysfunctions: possible cause of cell death in the nervous system. Physiol Res 52:269–274

    CAS  PubMed  Google Scholar 

  18. Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63

    Article  PubMed  CAS  Google Scholar 

  19. Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13:385–392

    Article  CAS  PubMed  Google Scholar 

  20. Manfredi G, Kawamata H (2016) Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis. Neurobiol Dis 90:35–42

    Article  CAS  PubMed  Google Scholar 

  21. Zhang H, Liu J, Sun S, Pchitskaya E, Popugaeva E, Bezprozvanny I (2015) Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer’s disease. J Alzheimer’s Dis 45:561–580

    CAS  Google Scholar 

  22. Hetz CA, Soto C (2006) Stressing out the ER: a role of the unfolded protein response in prion-related disorders. Curr Mol Med 6:37–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R (2008) Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27:6407–6418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zalk R, Lehnart SE, Marks AR (2007) Modulation of the ryanodine receptor and intracellular calcium. Annu Rev Biochem 76:367–385

    Article  CAS  PubMed  Google Scholar 

  25. Ferreiro E, Resende R, Costa R, Oliveira CR, Pereira CMF (2006) An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis 23:669–678

    Article  CAS  PubMed  Google Scholar 

  26. Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C (2003) Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 22:5435–5445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Credle JJ, Forcelli PA, Delannoy M, Oaks AW, Permaul E, Berry DL, Duka V, Wills J, Sidhu A (2015) α-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson’s disease. Neurobiology of Disease 76:112–125

    Article  CAS  PubMed  Google Scholar 

  28. Medina DL, Paola SD, Peluso I, Armani A, Stefani DD, Venditti R, Montefusco S, Scotto-Rosato A, Prezioso C, Forrester A, Settembre C, Wang W, Gao Q, Xu H, Sandri M, Rizzuto R, Ade Matteis M, Ballabio A (2015) Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat Cell Bio 17(3):288–299

    Article  CAS  Google Scholar 

  29. Tong Y, Song F (2015) Intracellular calcium signaling regulates autophagy via calcineurin mediated TFEB dephosphorylation. Autophagy 11(7):1192–1195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Klee CB, Draetta GF, Hubbard MJ (1988) Calcineurin. Adv Enzymol Relat Areas Mol Biol 61:149–200

    CAS  PubMed  Google Scholar 

  31. Aramburu J, Rao A, Klee CB (2000) Calcineurin: from structure to function. Curr Top Cell Regul 36:237–295

    Article  CAS  PubMed  Google Scholar 

  32. Rusnak F, Mertz P (2000) Calcineurin: form and function. Physiol Rev 80:1483–1521

    CAS  PubMed  Google Scholar 

  33. Molkentin JD (2001) Calcineurin, mitochondrial membrane potential, and cardiomyocyte apoptosis. Circ Res 88:1220–1222

    Article  CAS  PubMed  Google Scholar 

  34. Kissinger CR, Parge NE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kallish VJ, Tucker KD, Showalter RE, Moomaw EW, Gastinel LN, Habuka N, Chen X, Maldonado F, Barker JE, Bacquet R, Villafranca E (1995) Crystal structure of human calcineurin and the human FKBP12–FK506–calcineurin complex. Nature 378:641–644

    Article  CAS  PubMed  Google Scholar 

  35. Griffith JP, Kim JL, Kim BE, Simchak ND, Thomson JA, Fitzgibbon MJ, Flaming MA, Caron PR, Haiao K, Navia MA (1995) X-ray structure of calcineurin inhibited by the immunophilin—immunosuppressant FKBP12–FK506 complex. Cell 82:507–522

    Article  CAS  PubMed  Google Scholar 

  36. Huai Q, Kim HY, Liu Y, Zhao Y, Mondragon A, Liu J, Ke H (2002) Crystal structure of calcineurin–cyclophilin–cyclosporine shows common but distinct recognition of immunophilin–drug complexes. Proc Natl Acad Sci USA 99:12037–12042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jin L, Harrison SC (2002) Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin. Proc Natl Acad Sci USA 99:13522–13526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. J Goldberg, H. Huang, Y. Kwon, P. Greengard, A.C. Nairn, J. Kuriyan. Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1, Nature 376 (1995) 745–753

  39. Wang HL, Du YW, Xiang BQ, Lin WL, Wei Q (2007) The regulatory domains of CNA have different effects on the inhibition of CN activity by FK506 and CsA. IUBMB Life 59(6):388–393

    Article  CAS  PubMed  Google Scholar 

  40. Voegtli WC, White DJ, Reiter NJ, Rusnak F, Rosenzweig AC (2000) Structure of the bacteriophage Lambda Ser/Thr protein phosphatase with sulfate ion bound in two coordination modes. Biochemistry 39:15365

    Article  CAS  PubMed  Google Scholar 

  41. Klabunde T, Strater N, Frohlich R, Witzel H, Krebs B (1996) Mechanism of Fe(III)–Zn(II) purple acid phosphatase based on crystal structures. J Mol Biol 259:737–748

    Article  CAS  PubMed  Google Scholar 

  42. Ito A, Hashimoto T, Hirai M, Takeda T, Shuntoh H, Kuno T, Tanaka C (1989) The complete primary structure of calcineurin A, a calmodulin binding protein homologous with protein phosphatases1 and 2. Biochem Biophys Res Commun 163:1492–1497

    Article  CAS  PubMed  Google Scholar 

  43. Das AK, Helps NR, Cohen PTW, Barford D (1996) Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 A resolution. EMBO J 15:6798–6809

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hashimoto Y, King MM, Soderling TR (1988) Regulatory interactions of calmodulin-binding proteins: phosphorylation of calcineurin by autophosphorylated Ca2+/calmodulin-dependent protein kinase II. Proc Natl AcadSci USA 85:7001–7005

    Article  CAS  Google Scholar 

  45. Mukerjee N, McGinnis KM, Park YH, Gnegy ME, Wang KK (2000) Caspase-mediated proteolytic activation of calcineurin in thapsigargin-mediated apoptosis in SH-SY5Y neuroblastoma Cells. Arch Biochem Biophys 379:337–343

    Article  CAS  PubMed  Google Scholar 

  46. Wu HY, Tomizawa K, Matsui H (2007) Calpain-calcineurin signaling inthe pathogenesis of calcium-dependent disorder. Acta Med Okayama 61:123–137

    CAS  PubMed  Google Scholar 

  47. Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K, Gong CX (2005) Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 280:37755–37762

    Article  CAS  PubMed  Google Scholar 

  48. Winder DG, Mansuy IM, Osman M, Moallem TM, Kandel ER (1998) Genetic and pharmacological evidence for a novel intermediate phase of long-term potentiation suppressed by calcineurin. Cell 92:25–37

    Article  CAS  PubMed  Google Scholar 

  49. Swanson SK, Born T, Zydowsky LD, Cho H, Chang HY, Walsh CT, Rusnak F (1992) Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Proc Natl Acad Sci USA 89:3741–3745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Miyata S, Ohkubo Y, Mutoh S (2005) A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis. Inflamm Res 54:1–9

    Article  CAS  PubMed  Google Scholar 

  51. Tedesco D, Haragsim L (2012) Cyclosporine: a review. J Transplant 230386:1–7

    Article  CAS  Google Scholar 

  52. Shibasaki F, Hallin U, Uchino H (2002) Calcineurin as a multifunctional regulator. J Biochem 131:1–15

    Article  CAS  PubMed  Google Scholar 

  53. Mansuy IM (2003) Calcineurin in memory and bidirectional plasticity. Biochem Biophys Res Commun 311:1195–1208

    Article  CAS  PubMed  Google Scholar 

  54. Klee CB, Crouch TH, Krinks MH (1979) Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci USA 76:6270–6273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hubbard MJ, Klee CB (1987) Calmodulin binding by calcineurin ligand-induced renaturation of protein immobilized on nitrocellulose. J Biol Chem 262:15062–15070

    CAS  PubMed  Google Scholar 

  56. Armstrong DL (1989) Calcium channel regulation by calcineurin, a Ca2+-activated phosphatase in mammalian brain. Trends Neurosci 12:117–122

    Article  CAS  PubMed  Google Scholar 

  57. Zhu Y, Yakel JL (1997) Calcineurin modulates G protein-mediated inhibition of N-type calcium channels in rat sympathetic neurons. J Neurophysiol 78:1161–1165

    CAS  PubMed  Google Scholar 

  58. Burley JR, Sihra TS (2000) A modulatory role for protein phosphatase 2B (calcineurin) in the regulation of Ca2+ entry. Eur J Neurosci 12:2881–2891

    Article  CAS  PubMed  Google Scholar 

  59. Day M, Olson PA, Platzer J, Striessnig J, Surmeier DJ (2002) Stimulation of 5-HT(2) receptors in prefrontal pyramidal neurons inhibits Ca(v)1.2 L type Ca(2+) currents via a PLCbeta/IP3/calcineurin signaling cascade. J Neurophysiol 87:2490–2504

    CAS  PubMed  Google Scholar 

  60. Heindorff K, Baumann O (2014) Calcineurin is part of a negative feedback loop in the InsP3/Ca2+ signalling pathway in blowfly salivary glands. Cell Calcium 56:215–224

    Article  CAS  PubMed  Google Scholar 

  61. Haruhiko Bito, Deisseroth Karl, Tsien Richard W (1996) CREB phosphorylation and dephosphorylation: a Ca2+ and stimulus duration-dependent switch for hippocampal gene expression. Cell 87:1203–1214

    Article  Google Scholar 

  62. Graef IA, Wang F, Charron F, Chen L, Neilson J, Tessier-Lavigne M, Crabtree GR (2003) Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113:657–670

    Article  CAS  PubMed  Google Scholar 

  63. Groth RD, Mermelstein PG (2003) Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci 23:8125–8134

    CAS  PubMed  Google Scholar 

  64. Shalizi A, Gaudilliere B, Yuan Z, Stegmuller J, Shirogane T, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A (2006) A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311:1012–1017

    Article  CAS  PubMed  Google Scholar 

  65. Flavell SW, Cowan CW, Kim TK, Greer PL, Lin Y, Paradis S, Griffith EC, Hu LS, Chen C, Greenberg ME (2006) Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311:1008–1012

    Article  CAS  PubMed  Google Scholar 

  66. Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D, Blair LA, Marshall J, Mao Z (2003) Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38:33–46

    Article  CAS  PubMed  Google Scholar 

  67. García E, Stracher A, Jay D (2006) Calcineurin dephosphorylates the C-terminal region of lamin in an important regulatory site: a possible mechanism for lamin mobilization and cell signaling. Arch Biochem Biophys 446:140–150

    Article  PubMed  CAS  Google Scholar 

  68. Chen Y, Holstein DM, Aime S, Bollo M, Lechleiter JD (2016) Calcineurin β protects brain after injury by activating the unfolded protein response. Neurobiol Dis 94:139–156

    Article  CAS  PubMed  Google Scholar 

  69. Kim S, Violette CJ, Ziff EB (2015) Reduction of increased calcineurin activity rescues impaired homeostatic synaptic plasticity in presenilin 1 M146V mutant. Neurobiol Aging 36:3239–3246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tangmansakulchai K, Abubakar Z, Kitiyanant N, Suwanjang W, Leepiyasakulchai C, Govitrapong P, Chetsawang B (2016) Calpastatin overexpression reduces oxidative stress-induced mitochondrial impairment and cell death in human neuroblastoma SH-SY5Y cells by decreasing calpain and calcineurin activation, induction of mitochondrial fission and destruction of mitochondrialfusion. Mitochondrion. doi:10.1016/j.mito.2016.07.009

    PubMed  Google Scholar 

  71. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  CAS  PubMed  Google Scholar 

  72. Wishart TM, Parson SH, Gillingwater TH (2006) Synaptic vulnerability in neurodegenerative disease. J Neuropathol ExpNeurol 65:733–739

    Article  CAS  Google Scholar 

  73. Mallucci GR (2009) Prion neurodegeneration: starts and stops at the synapse. Prion 3:195–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang Y, Zhao D, Pan B, Song Z, Shah SZA, Yin X, Zhou X, Yang L (2015) Death receptor 6 and caspase-6 regulate prion peptide-induced axonal degeneration in rat spinal neurons. J Mol Neurosci 56(4):966–976

    Article  CAS  PubMed  Google Scholar 

  75. Karsten Baumgartel, Mansuy Isabelle M (2012) Neural functions of calcineurin in synaptic plasticity and memory. Learn Memory 19:375–384

    Article  CAS  Google Scholar 

  76. Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 3:661–669

    Article  CAS  PubMed  Google Scholar 

  77. Mansuy IM, Mayford M, Jacob B, Kandel ER, Bach ME (1998) Restricted and regulated overexpression reveals calcineurin as a keycomponent in the transition from short-term to long-termmemory. Cell 92:39–49

    Article  CAS  PubMed  Google Scholar 

  78. Malleret G, Haditsch U, Genoux D, Jones MW, Bliss TV, Vanhoose AM, Weitlauf C, Kandel ER, Winder DG, Mansuy IM (2001) Inducible and reversible enhancement of learning, memory and long-term potentiation by genetic inhibition of calcineurin. Cell 104:675–686

    Article  CAS  PubMed  Google Scholar 

  79. Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miyakawa T, Bear MF, Tonegawa S (2001) Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 107:617–629

    Article  CAS  PubMed  Google Scholar 

  80. Zhao WQ, Santini F, Breese R, Ross D, Zhang XD, Stone DJ, Ferrer M, Townsend M, Wolfe AL, Seager MA et al (2010) Inhibition of calcineurin-mediated endocytosis and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid beta oligomer-induced synaptic disruption. J Biol Chem 285:7619–7632

    Article  CAS  PubMed  Google Scholar 

  81. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875

    Article  CAS  PubMed  Google Scholar 

  82. Taglialatela G, Hogan D, Zhang WR, Dineley KT (2009) Intermediate and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav Brain Res 200:95–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Stockwell J, Chen Z, Niazi M, Nosib S, Cayabyab FS (2016) Protein phosphatase role in adenosine A1 receptor-induced AMPA receptor trafficking and rat hippocampal neuronal damage in hypoxia/reperfusion injury. Neuropharmacology 102:254–265

    Article  CAS  PubMed  Google Scholar 

  84. Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20:709–726

    Article  CAS  PubMed  Google Scholar 

  85. Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861

    Article  CAS  PubMed  Google Scholar 

  86. Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623

    Article  CAS  PubMed  Google Scholar 

  87. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642

    Article  CAS  PubMed  Google Scholar 

  88. Benito E, Barco A (2010) CREB’s control of intrinsic and synapticplasticity: implications for CREB-dependent memory models. Trends Neurosci 33:230–240

    Article  CAS  PubMed  Google Scholar 

  89. Agostinho P, Lopes JP, Velez Z, Oliveira CR (2008) Overactivation of calcineurin induced by amyloid-beta and prion proteins. Neurochem Int 52:1226–1233

    Article  CAS  PubMed  Google Scholar 

  90. Reese LC, Zhang W, Dineley KT, Kayed R, Taglialatela G (2008) Selective induction of calcineurin activity and signaling by oligomeric amyloid beta. Aging Cell 7:824–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dineley KT, Kayed R, Neugebauer V, Fu Y, Zhang W, Reese LC, Taglialatela G (2010) Amyloid beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice. J Neurosci Res. 88(13):2923–2932

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Spires-Jones TL, Kay K, Matsouka R, Rozkalne A, Betensky RA, Hyman BT (2011) Calcineurin inhibition with systemic FK506 treatment increases dendritic branching and dendritic spine density in healthy adult mouse brain. Neurosci Lett 487:260–263

    Article  CAS  PubMed  Google Scholar 

  93. Yamamoto-Sasaki M, Ozawa H, Saito T, Rösler M, Riederer P (1999) Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Res 824:300–303

    Article  CAS  PubMed  Google Scholar 

  94. Taglialatela G, Cristiana R, Luca C (2015) Reduced incidence of dementia in solid organ transplant patients treated with calcineurin inhibitors. J Alzheimer’s Dis 47:329–333

    Article  CAS  Google Scholar 

  95. Kingsbury TJ, Bambrick LL, Roby CD, Krueger BK (2007) Calcineurin activity is required for depolarization-induced CREB dependentgene transcription in cortical neurons. J Neurochem 103:761–770

    Article  CAS  PubMed  Google Scholar 

  96. Lam BY, Zhang W, Enticknap N, Haggis E, Cader MZ, Chawla S (2009) Inverse regulation of plasticity-related immediate early genes by calcineurin in hippocampal neurons. J Biol Chem 284:12562–12571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ (2008) Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59:214–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Greengard P, Valtorta F, Czernik AJ, Benfenati F (1993) Synaptic vesicle phosphor proteins and regulation of synaptic function. Science 259:780–785

    Article  CAS  PubMed  Google Scholar 

  99. Hosaka M, Hammer RE, Sudhof TC (1999) A phospho-switch controls the dynamic association of synapsins with synaptic vesicles. Neuron 24:377–387

    Article  CAS  PubMed  Google Scholar 

  100. Jovanovic JN, Sihra TS, Nairn AC, Hemmings HC Jr, Greengard P, Czernik AJ (2001) Opposing changes in phosphorylation of specific sites in synapsin I during Ca2+-dependent glutamate release in isolated nerve terminals. J Neurosci 21:7944–7953

    CAS  PubMed  Google Scholar 

  101. Pleiss MM, Sompol P, Kraner SD, Abdul HM, Furman JL, Guttmann RP, Wilcock DM, Nelson PT, Norris CM (1862) Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function. Biochimica et Biophysica Acta 2016:1521–1532

    Google Scholar 

  102. Klumpp S, Krieglstein J (2002) Serine/threonine protein phosphatases in apoptosis. Curr Opin Pharmacol 2:458–462

    Article  CAS  PubMed  Google Scholar 

  103. Shou Y, Li L, Prabhakaran K, Borowitz JL, Isom GE (2004) Calcineurin mediated Bad translocation regulates cyanide-induced neuronal apoptosis. Biochem J 379:805–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yang L, Omori K, Suzukawa J, Inagaki C (2004) Calcineurin-mediated BAD Ser155 dephosphorylation in ammonia-induced apoptosis of cultured rat hippocampal neurons. Neurosci Lett 357:73–75

    Article  CAS  PubMed  Google Scholar 

  105. Strasser A, O’Connor L, Dixit VM (2000) Apoptosis signaling. Annu Rev Biochem 69:217–245

    Article  CAS  PubMed  Google Scholar 

  106. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL et al (2010) Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 30:2636–2649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nguyen T, Di Giovanni S (2008) NFAT signaling in neural development and axon growth. Int J Dev Neurosci 26:141–145

    Article  CAS  PubMed  Google Scholar 

  108. Ni C, Li Z, Qian M, Zhou Y, Wang J, Guo X (2015) Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling. Biochem Biophys Res Commun 460:889–895

    Article  CAS  PubMed  Google Scholar 

  109. Moreno M, Fernández V, Monllau JM, Borrell V, Lerin C, de la Iglesia N (2015) Transcriptional profiling of hypoxic neural stem cells identifies calcineurin-NFATc4 signaling as a major regulator of neural stem cell biology. Stem Cell Rep 5:157–165

    Article  CAS  Google Scholar 

  110. Sun X, Wu Y, Herculano B, Song W (2014) RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis. PLoS One 9(4):e95471

    Article  PubMed  PubMed Central  Google Scholar 

  111. Martina L, Latypova X, Wilsona CM, Magnaudeix A, Perrin M-L, Terro F (2013) Tau protein phosphatases in Alzheimer’s disease: The leading role of PP2A. Ageing Res Rev 12:39–49

    Article  CAS  Google Scholar 

  112. Yu D, Tong L, Song G, Lin W, Zhang L, Bai W, Gong H, Yin Y, Wei Q (2008) Tau binds both subunits of calcineurin, and binding is impaired by calmodulin. Biochimica et Biophysica Acta 1783:2255–2261

    Article  CAS  PubMed  Google Scholar 

  113. Karch CM, Jeng AT, Goate AM (2013) Calcium phosphatase calcineurin influences tau metabolism. Neurobiol Aging 34:374–386

    Article  CAS  PubMed  Google Scholar 

  114. Luo J, Ma J, Da-Yu Y, Fan B, Zhang W, Ling-Hui T, Wei Q (2008) Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain. Brain Res Bull 76:464–468

    Article  CAS  PubMed  Google Scholar 

  115. Luo J, Sun L, Lin X, Liu G, Yu J, Parisiadou L, Xie C, Ding J, Cai H (2014) A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons. Hum Mol Genet 23(24):6567–6574. doi:10.1093/hmg/ddu377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Caraveo G, Auluck PK, Whitesell L, Chung CY, Baru V, Mosharov EV, Yan X, Ben-Johny MU, Soste M, Picotti P, Kim H, Caldwell KA, Caldwell GA, Sulzer D, Yue DT, Lindquist S (2014) Calcineurin determines toxic versus beneficial responses to α synuclein. Proc Natl Acad Sci 111(34):E3544–E3552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mineur YS, Taylor SR, Picciotto MR (2014) Calcineurin downregulation in the amygdala is sufficient to induce anxiety-like and depression-like behaviors in C57BL/6J male mice. Biol Psychiatry 75:991–998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Humbert S, Saudou F (2005) Huntington’s disease: intracellular signaling pathways and neuronal death. J Soc Biol 199(3):247–251

    Article  CAS  PubMed  Google Scholar 

  119. Gratuze M, Noel A, Julien C, Cisbani G, Millot-Rousseau P, Morin F, Dickler M, Goupil C, Bezeau F, Poitras I, Bissonnette S, Whittington RA, Hebert SS, Ciccechetti F, Parker JA, Samadi P, Planel E (2014) Tau hyperphosphorylation and deregulation of calcineurin in mouse model of huntington’s disease. Hum Mol Genet 24(1):86–99

    Article  PubMed  CAS  Google Scholar 

  120. Ermak G, Hench KJ, Chang KT, Sachdev S, Davies KJ (2009) Regulator of calcineurin (RCAN1-1L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro. J Biol Chem 284:11845–11853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Takehiro N, Satoh K, Ishibashi D, Fuse T, Sano K, Kamatari YO, Kuwata K, Shigematsu K, Iwamaru Y, Takenouchi T, Kitani H, Atarashi NNR (2013) FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice. Autophagy 9(9):1386–1394

    Article  CAS  Google Scholar 

  122. Kishi T, Ikeda A, Nagao R, Koyama N (2007) The SCFCdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin. Proc Natl Acad Sci 104(44):17418–17423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mulero MC, Aubareda A, Schlüter A, Pérez-Riba M (2007) RCAN3, a novel calcineurin inhibitor that down-regulates NFAT-dependent cytokine gene expression. Biochimica et Biophysica Acta 1773:330–341

    Article  CAS  PubMed  Google Scholar 

  124. Gelpi RJ, Gao S, Zhai P, Yan L, Hong C, Danridge LMA, Ge H, Maejima Y, Donato M, Yokota M, Molkentin JD, Vatner DE, Vatner SF, Sadoshima J (2009) Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload. Am J Physiol Heart Circ Physiol 297:H1814–H1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sobrado M, Ramirez BG, Neria F, Lizasoain I, Arbones ML, Minami T, Redondo JM, Moro MÁ, Cano E (2012) Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury. J Neuroinflamm 9(48):1–13

    Google Scholar 

  126. Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, Merson TD, Bourne JA, Porta S, Arbonés ML, Finkelstein DI, Pritchard MA (2012) Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory. Hum Mol Genet 21(13):3025–3041

    Article  CAS  PubMed  Google Scholar 

  127. Wong H, Levenga J, Cain P, Rothermel B, Klann E, Hoeffer C (2015) RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer’s diseas. Acta Neuropathol 130:829–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Patel A, Yamashita N, Ascan M, Bodmer D, Boehm E, Bodkin-Clarke C, Ryu YK, Kuruvilla R (2015) RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in down syndrome. Nat Commun. doi:10.1038/ncomms10119

    Google Scholar 

  129. Zhao Y, Yan H, Happeck R, Peiter-Volk T, Xu H, Zhang Y, Peiter E, van Oostende Triplet C, Whiteway M, Jiang L (2016) The plasma membrane protein Rch1 is a negative regulator of cytosolic calcium homeostasis and positively regulated by the calcium/calcineurin signaling pathway in budding yeast. Eur J Cell Biol 95(3–5):164–174

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to Professor Giulio Taglialatela, Director, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch for helpful comments during preparation of the manuscript.

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Authors and Affiliations

  1. National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, 100193, China

    Syed Zahid Ali Shah, Tariq Hussain, Deming Zhao & Lifeng Yang

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  1. Syed Zahid Ali Shah
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  2. Tariq Hussain
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  3. Deming Zhao
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  4. Lifeng Yang
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Correspondence to Lifeng Yang.

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According to the journal’s requirement we hereby declare that it is a review article where no animal or human experiments were conducted; we followed the strict ethical rules according to compilation of already published data on the current topic.

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All the authors declare that there are no competing interests amongst them.

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This work was supported by the Natural Science Foundation of China (Project Nos. 31272532 and 31172293).

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Shah, S.Z.A., Hussain, T., Zhao, D. et al. A central role for calcineurin in protein misfolding neurodegenerative diseases. Cell. Mol. Life Sci. 74, 1061–1074 (2017). https://doi.org/10.1007/s00018-016-2379-7

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