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Molecular Neurobiology

, Volume 50, Issue 3, pp 1085–1097 | Cite as

Aberrant Expression of RCAN1 in Alzheimer’s Pathogenesis: A New Molecular Mechanism and a Novel Drug Target

  • Yili Wu
  • Philip T. T. Ly
  • Weihong SongEmail author
Article

Abstract

AD, a devastating neurodegenerative disorder, is the most common cause of dementia in the elderly. Patients with AD are characterized by three hallmarks of neuropathology including neuritic plaque deposition, neurofibrillary tangle formation, and neuronal loss. Growing evidences indicate that dysregulation of regulator of calcineurin 1 (RCAN1) plays an important role in the pathogenesis of AD. Aberrant RCAN1 expression facilitates neuronal apoptosis and Tau hyperphosphorylation, leading to neuronal loss and neurofibrillary tangle formation. This review aims to describe the recent advances of the regulation of RCAN1 expression and its physiological functions. Moreover, the AD risk factors-induced RCAN1 dysregulation and its role in promoting neuronal loss, synaptic impairments and neurofibrillary tangle formation are summarized. Furthermore, we provide an outlook into the effects of RCAN1 dysregulation on APP processing, Aβ generation and neuritic plaque formation, and the possible underlying mechanisms, as well as the potential of targeting RCAN1 as a new therapeutic approach.

Keyword

Alzheimer’s disease Amyloid β protein Apoptosis RCAN1 Tau hyperphosphorylation 

Abbreviations

AD

Alzheimer’s disease

RCAN1

Regulator of calcineurin 1

Notes

Acknowledgments

This work was supported by Canadian Institutes of Health Research (CIHR) Operating Grant TAD-117948. W.S. is the holder of the Tier 1 Canada Research Chair in Alzheimer's Disease.

References

  1. 1.
    ADI (2010) World Alzheimer Report 2010. http://www.alzcouk/research/files/WorldAlzheimerReport2010pdf
  2. 2.
    Alzheimer'sAssociation (2012) 2012 Alzheimer's disease facts and figures. Alzheimers Dement 8(2):131–168Google Scholar
  3. 3.
    Delacourte A, Defossez A (1986) Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J Neurol Sci 76(2–3):173–186PubMedGoogle Scholar
  4. 4.
    Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261(13):6084–6089PubMedGoogle Scholar
  5. 5.
    Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83(13):4913–4917PubMedCentralPubMedGoogle Scholar
  6. 6.
    Ihara Y, Nukina N, Miura R, Ogawara M (1986) Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 99(6):1807–1810PubMedGoogle Scholar
  7. 7.
    Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A 83(11):4044–4048Google Scholar
  8. 8.
    Wood JG, Mirra SS, Pollock NJ, Binder LI (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci U S A 83(11):4040–4043PubMedCentralPubMedGoogle Scholar
  9. 9.
    Glenner GG, Wong CW (1984) Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122(3):1131–1135PubMedGoogle Scholar
  10. 10.
    Glenner GG, Wong CW, Quaranta V, Eanes ED (1984) The amyloid deposits in Alzheimer's disease: their nature and pathogenesis. Appl Pathol 2(6):357–369PubMedGoogle Scholar
  11. 11.
    Glenner GG, Wong CW (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890PubMedGoogle Scholar
  12. 12.
    Mattson MP (2004) Pathways towards and away from Alzheimer's disease. Nature 430(7000):631–639PubMedCentralPubMedGoogle Scholar
  13. 13.
    Sun X, Bromley-Brits K, Song W (2012) Regulation of beta-site APP-cleaving enzyme 1 gene expression and its role in Alzheimer's disease. J Neurochem 120(Suppl 1):62–70Google Scholar
  14. 14.
    Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA (1988) Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A 85(13):4884–4888PubMedCentralPubMedGoogle Scholar
  15. 15.
    Wischik CM, Novak M, Thogersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A 85(12):4506–4510PubMedCentralPubMedGoogle Scholar
  16. 16.
    Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A 85(11):4051–4055PubMedCentralPubMedGoogle Scholar
  17. 17.
    Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 72(5):1858–1862PubMedCentralPubMedGoogle Scholar
  18. 18.
    Liu Z, Lv C, Zhao W, Song Y, Pei D, Xu T (2012) NR2B-Containing NMDA receptors expression and their relationship to apoptosis in hippocampus of Alzheimer's disease-like rats. Neurochem Res 37(7):1420–1427PubMedGoogle Scholar
  19. 19.
    Lukiw WJ, Bazan NG (2010) Inflammatory, apoptotic, and survival gene signaling in Alzheimer's disease. A review on the bioactivity of neuroprotectin D1 and apoptosis. Mol Neurobiol 42(1):10–16PubMedGoogle Scholar
  20. 20.
    Takuma K, Kataoka S, Ago Y, Matsuda T (2009) Mitochondrial dysfunction and neuronal apoptosis: new molecular approach to prevent Alzheimer's disease. Nihon Yakurigaku Zasshi 134(4):180–183PubMedGoogle Scholar
  21. 21.
    Bertoni-Freddari C, Fattoretti P, Casoli T, Di Stefano G, Balietti M, Giorgetti B, Perretta G (2009) Neuronal apoptosis in Alzheimer's disease: the role of age-related mitochondrial metabolic competence. Ann N Y Acad Sci 1171:18–24PubMedGoogle Scholar
  22. 22.
    Kitamura Y, Shimohama S, Kamoshima W, Matsuoka Y, Nomura Y, Taniguchi T (1997) Changes of p53 in the brains of patients with Alzheimer's disease. Biochem Biophys Res Commun 232(2):418–421PubMedGoogle Scholar
  23. 23.
    Su JH, Deng G, Cotman CW (1997) Bax protein expression is increased in Alzheimer's brain: correlations with DNA damage, Bcl-2 expression, and brain pathology. J Neuropathol Exp Neurol 56(1):86–93PubMedGoogle Scholar
  24. 24.
    Guo Q, Fu W, Xie J, Luo H, Sells SF, Geddes JW, Bondada V, Rangnekar VM, Mattson MP (1998) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med 4(8):957–962PubMedGoogle Scholar
  25. 25.
    Kitamura Y, Shimohama S, Kamoshima W, Ota T, Matsuoka Y, Nomura Y, Smith MA, Perry G, Whitehouse PJ, Taniguchi T (1998) Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease. Brain Res 780(2):260–269PubMedGoogle Scholar
  26. 26.
    Engidawork E, Gulesserian T, Yoo BC, Cairns N, Lubec G (2001) Alteration of caspases and apoptosis-related proteins in brains of patients with Alzheimer's disease. Biochem Biophys Res Commun 281(1):84–93PubMedGoogle Scholar
  27. 27.
    Gulesserian T, Engidawork E, Yoo BC, Cairns N, Lubec G (2001) Alteration of caspases and other apoptosis regulatory proteins in Down syndrome. J Neural Transm Suppl 61:163–179PubMedGoogle Scholar
  28. 28.
    Su JH, Zhao M, Anderson AJ, Srinivasan A, Cotman CW (2001) Activated caspase-3 expression in Alzheimer's and aged control brain: correlation with Alzheimer pathology. Brain Res 898(2):350–357PubMedGoogle Scholar
  29. 29.
    Down JLH (1866) Observations on an ethnic classification of idiots. Lond Hosp Rep 3:259–262Google Scholar
  30. 30.
    Jacobs PA, Baikie AG, Court Brown WM, Strong JA (1959) The somatic chromosomes in mongolism. Lancet 1(7075):710PubMedGoogle Scholar
  31. 31.
    Lejeune J, Gautier M, Turpin R (1959) Study of somatic chromosomes from 9 mongoloid children. C R Hebd Seances Acad Sci 248(11):1721–1722PubMedGoogle Scholar
  32. 32.
    Janicki MP, Dalton AJ (2000) Prevalence of dementia and impact on intellectual disability services. Ment Retard 38(3):276–288Google Scholar
  33. 33.
    Smith DS (1998) Down syndrome and incidence of Alzheimer's disease. Am Fam Physician 57(7):1498PubMedGoogle Scholar
  34. 34.
    Menendez M (2005) Down syndrome, Alzheimer's disease and seizures. Brain Dev 27(4):246–252PubMedGoogle Scholar
  35. 35.
    Ermak G, Sojitra S, Yin F, Cadenas E, Cuervo AM, Davies KJ (2012) Chronic expression of RCAN1-1 L protein induces mitochondrial autophagy and metabolic shift from oxidative phosphorylation to glycolysis in neuronal cells. J Biol Chem 287(17):14088–14098Google Scholar
  36. 36.
    Harris CD, Ermak G, Davies KJ (2007) RCAN1-1 L is overexpressed in neurons of Alzheimer's disease patients. FEBS J 274(7):1715–1724PubMedGoogle Scholar
  37. 37.
    Sun X, Wu Y, Chen B, Zhang Z, Zhou W, Tong Y, Yuan J, Xia K, Gronemeyer H, Flavell RA, Song W (2011) Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase-3 activation. J Biol Chem 286(11):9049–9062PubMedCentralPubMedGoogle Scholar
  38. 38.
    Dierssen M, Arque G, McDonald J, Andreu N, Martinez-Cue C, Florez J, Fillat C (2011) Behavioral characterization of a mouse model overexpressing DSCR1/RCAN1. PLoS One 6(2):e17010PubMedCentralPubMedGoogle Scholar
  39. 39.
    Lloret A, Badia MC, Giraldo E, Ermak G, Alonso MD, Pallardo FV, Davies KJ, Vina J (2011) Amyloid-beta toxicity and Tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease. J Alzheimers Dis 27(4):701–709PubMedCentralPubMedGoogle Scholar
  40. 40.
    Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, Merson TD, Bourne JA, Porta S, Arbones 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):3025–3041PubMedGoogle Scholar
  41. 41.
    Wu Y, Song W (2013) Regulation of RCAN1 translation and its role in oxidative stress-induced apoptosis. FASEB J 27(1):208–221PubMedGoogle Scholar
  42. 42.
    Lee EJ, Lee JY, Seo SR, Chung KC (2007) Overexpression of DSCR1 blocks zinc-induced neuronal cell death through the formation of nuclear aggregates. Mol Cell Neurosci 35(4):585–595PubMedGoogle Scholar
  43. 43.
    Ermak G, Pritchard MA, Dronjak S, Niu B, Davies KJ (2011) Do RCAN1 proteins link chronic stress with neurodegeneration? FASEB J 25(10):3306–3311PubMedCentralPubMedGoogle Scholar
  44. 44.
    Ermak G, Harris CD, Battocchio D, Davies KJ (2006) RCAN1 (DSCR1 or Adapt78) stimulates expression of GSK-3beta. FEBS J 273(10):2100–2109PubMedGoogle Scholar
  45. 45.
    Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X (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(10):1935–1944PubMedGoogle Scholar
  46. 46.
    Fuentes JJ, Pritchard MA, Estivill X (1997) Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Genomics 44(3):358–361PubMedGoogle Scholar
  47. 47.
    Crawford DR, Leahy KP, Abramova N, Lan L, Wang Y, Davies KJ (1997) Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress. Arch Biochem Biophys 342(1):6–12PubMedGoogle Scholar
  48. 48.
    Genesca L, Aubareda A, Fuentes JJ, Estivill X, De La Luna S, Perez-Riba M (2003) Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life. Biochem J 374(Pt 2):567–575PubMedCentralPubMedGoogle Scholar
  49. 49.
    Fuentes JJ, Genesca L, Kingsbury TJ, Cunningham KW, Perez-Riba M, Estivill X, de la Luna S (2000) DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 9(11):1681–1690PubMedGoogle Scholar
  50. 50.
    Abbasi S, Lee JD, Su B, Chen X, Alcon JL, Yang J, Kellems RE, Xia Y (2006) Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1. J Biol Chem 281(12):7717–7726PubMedGoogle Scholar
  51. 51.
    Lee EJ, Seo SR, Um JW, Park J, Oh Y, Chung KC (2008) NF-kappaB-inducing kinase phosphorylates and blocks the degradation of Down syndrome candidate region 1. J Biol Chem 283(6):3392–3400PubMedGoogle Scholar
  52. 52.
    Liu Q, Busby JC, Molkentin JD (2009) Interaction between TAK1–TAB1–TAB2 and RCAN1-calcineurin defines a signalling nodal control point. Nat Cell Biol 11(2):154–161PubMedCentralPubMedGoogle Scholar
  53. 53.
    Vega RB, Yang J, Rothermel BA, Bassel-Duby R, Williams RS (2002) Multiple domains of MCIP1 contribute to inhibition of calcineurin activity. J Biol Chem 277(33):30401–30407PubMedGoogle Scholar
  54. 54.
    Jung MS, Park JH, Ryu YS, Choi SH, Yoon SH, Kwen MY, Oh JY, Song WJ, Chung SH (2011) Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation. J Biol Chem 286(46):40401–40412PubMedCentralPubMedGoogle Scholar
  55. 55.
    Kim SS, Oh Y, Chung KC, Seo SR (2012) Protein kinase A phosphorylates Down syndrome critical region 1 (RCAN1). Biochem Biophys Res Commun 418(4):657–661PubMedGoogle Scholar
  56. 56.
    Ma L, Tang H, Ren Y, Deng H, Wu J, Wang Z (2012) p38alpha MAP kinase phosphorylates RCAN1 and regulates its interaction with calcineurin. Sci China Life Sci 55(7):559–566PubMedGoogle Scholar
  57. 57.
    Strippoli P, Lenzi L, Petrini M, Carinci P, Zannotti M (2000) A new gene family including DSCR1 (Down Syndrome Candidate Region 1) and ZAKI-4: characterization from yeast to human and identification of DSCR1-like 2, a novel human member (DSCR1L2). Genomics 64(3):252–263PubMedGoogle Scholar
  58. 58.
    Rothermel B, Vega RB, Yang J, Wu H, Bassel-Duby R, Williams RS (2000) A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J Biol Chem 275(12):8719–8725PubMedGoogle Scholar
  59. 59.
    Pfister SC, Machado-Santelli GM, Han SW, Henrique-Silva F (2002) Mutational analyses of the signals involved in the subcellular location of DSCR1. BMC Cell Biol 3:24PubMedCentralPubMedGoogle Scholar
  60. 60.
    Leahy KP, Crawford DR (2000) adapt78 protects cells against stress damage and suppresses cell growth. Arch Biochem Biophys 379(2):221–228PubMedGoogle Scholar
  61. 61.
    Michtalik HJ, Narayan AV, Bhatt N, Lin HY, Mulligan MT, Zhang SL, Crawford DR (2004) Multiple oxidative stress-response members of the Adapt78 family. Free Radic Biol Med 37(4):454–462PubMedGoogle Scholar
  62. 62.
    Casas C, Martinez S, Pritchard MA, Fuentes JJ, Nadal M, Guimera J, Arbones M, Florez J, Soriano E, Estivill X, Alcantara S (2001) Dscr1, a novel endogenous inhibitor of calcineurin signaling, is expressed in the primitive ventricle of the heart and during neurogenesis. Mech Dev 101(1–2):289–292PubMedGoogle Scholar
  63. 63.
    Rothermel BA, McKinsey TA, Vega RB, Nicol RL, Mammen P, Yang J, Antos CL, Shelton JM, Bassel-Duby R, Olson EN, Williams RS (2001) Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A 98(6):3328–3333PubMedCentralPubMedGoogle Scholar
  64. 64.
    van Rooij E, Doevendans PA, Crijns HJ, Heeneman S, Lips DJ, van Bilsen M, Williams RS, Olson EN, Bassel-Duby R, Rothermel BA, De Windt LJ (2004) MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction. Circ Res 94(3):e18–e26PubMedGoogle Scholar
  65. 65.
    Chan B, Greenan G, McKeon F, Ellenberger T (2005) Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo. Proc Natl Acad Sci U S A 102(37):13075–13080PubMedCentralPubMedGoogle Scholar
  66. 66.
    Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, Carinci P, Min KT, Fox DS, Cunningham KW, Bassel-Duby R, Olson EN, Zhang Z, Williams RS, Gerber HP, Perez-Riba M, Seo H, Cao X, Klee CB, Redondo JM, Maltais LJ, Bruford EA, Povey S, Molkentin JD, McKeon FD, Duh EJ, Crabtree GR, Cyert MS, de la Luna S, Estivill X (2007) Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J 21(12):3023–3028PubMedGoogle Scholar
  67. 67.
    Rusnak F, Mertz P (2000) Calcineurin: form and function. Physiol Rev 80(4):1483–1521PubMedGoogle Scholar
  68. 68.
    Klee CB, Crouch TH, Krinks MH (1979) Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci U S A 76(12):6270–6273PubMedCentralPubMedGoogle Scholar
  69. 69.
    Cottrell JR, Levenson JM, Kim SH, Gibson HE, Richardson KA, Sivula M, Li B, Ashford CJ, Heindl KA, Babcock RJ, Rose DM, Hempel CM, Wiig KA, Laeng P, Levin ME, Ryan TA, Gerber DJ (2013) Working memory impairment in calcineurin knock-out mice is associated with alterations in synaptic vesicle cycling and disruption of high-frequency synaptic and network activity in prefrontal cortex. J Neurosci 33(27):10938–10949PubMedCentralPubMedGoogle Scholar
  70. 70.
    Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, Crabtree GR, Kim SK (2006) Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature 443(7109):345–349PubMedGoogle Scholar
  71. 71.
    Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S (2003) Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci U S A 100(15):8987–8992PubMedCentralPubMedGoogle Scholar
  72. 72.
    Kingsbury TJ, Cunningham KW (2000) A conserved family of calcineurin regulators. Genes Dev 14(13):1595–1604PubMedCentralPubMedGoogle Scholar
  73. 73.
    Hilioti Z, Gallagher DA, Low-Nam ST, Ramaswamy P, Gajer P, Kingsbury TJ, Birchwood CJ, Levchenko A, Cunningham KW (2004) GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Genes Dev 18(1):35–47PubMedCentralPubMedGoogle Scholar
  74. 74.
    Shin SY, Yang HW, Kim JR, Do Heo W, Cho KH (2011) A hidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling network. J Cell Sci 124(Pt 1):82–90PubMedGoogle Scholar
  75. 75.
    Lee JI, Dhakal BK, Lee J, Bandyopadhyay J, Jeong SY, Eom SH, Kim DH, Ahnn J (2003) The Caenorhabditis elegans homologue of Down syndrome critical region 1, RCN-1, inhibits multiple functions of the phosphatase calcineurin. J Mol Biol 328(1):147–156PubMedGoogle Scholar
  76. 76.
    Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S (2009) Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459(7250):1126–1130PubMedCentralPubMedGoogle Scholar
  77. 77.
    Hill JA, Rothermel B, Yoo KD, Cabuay B, Demetroulis E, Weiss RM, Kutschke W, Bassel-Duby R, Williams RS (2002) Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. J Biol Chem 277(12):10251–10255PubMedGoogle Scholar
  78. 78.
    Sanna B, Brandt EB, Kaiser RA, Pfluger P, Witt SA, Kimball TR, van Rooij E, De Windt LJ, Rothenberg ME, Tschop MH, Benoit SC, Molkentin JD (2006) Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitators in vivo. Proc Natl Acad Sci U S A 103(19):7327–7332PubMedCentralPubMedGoogle Scholar
  79. 79.
    Vega RB, Rothermel BA, Weinheimer CJ, Kovacs A, Naseem RH, Bassel-Duby R, Williams RS, Olson EN (2003) Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy. Proc Natl Acad Sci U S A 100(2):669–674PubMedCentralPubMedGoogle Scholar
  80. 80.
    Hoeffer CA, Dey A, Sachan N, Wong H, Patterson RJ, Shelton JM, Richardson JA, Klann E, Rothermel BA (2007) The Down syndrome critical region protein RCAN1 regulates long-term potentiation and memory via inhibition of phosphatase signaling. J Neurosci 27(48):13161–13172PubMedGoogle Scholar
  81. 81.
    Lee JE, Jang H, Cho EJ, Youn HD (2009) Down syndrome critical region 1 enhances the proteolytic cleavage of calcineurin. Exp Mol Med 41(7):471–477PubMedCentralPubMedGoogle Scholar
  82. 82.
    Abbasi S, Su B, Kellems RE, Yang J, Xia Y (2005) The essential role of MEKK3 signaling in angiotensin II-induced calcineurin/nuclear factor of activated T-cells activation. J Biol Chem 280(44):36737–36746PubMedGoogle Scholar
  83. 83.
    Minami T, Horiuchi K, Miura M, Abid MR, Takabe W, Noguchi N, Kohro T, Ge X, Aburatani H, Hamakubo T, Kodama T, Aird WC (2004) Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem 279(48):50537–50554PubMedGoogle Scholar
  84. 84.
    Lee HJ, Kim YS, Sato Y, Cho YJ (2009) RCAN1-4 knockdown attenuates cell growth through the inhibition of Ras signaling. FEBS Lett 583(15):2557–2564PubMedGoogle Scholar
  85. 85.
    Ermak G, Harris CD, Davies KJ (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(8):814–824PubMedGoogle Scholar
  86. 86.
    Iizuka M, Abe M, Shiiba K, Sasaki I, Sato Y (2004) Down syndrome candidate region 1, a downstream target of VEGF, participates in endothelial cell migration and angiogenesis. J Vasc Res 41(4):334–344PubMedGoogle Scholar
  87. 87.
    Asai A, Qiu J, Narita Y, Chi S, Saito N, Shinoura N, Hamada H, Kuchino Y, Kirino T (1999) High level calcineurin activity predisposes neuronal cells to apoptosis. J Biol Chem 274(48):34450–34458PubMedGoogle Scholar
  88. 88.
    Ankarcrona M, Dypbukt JM, Orrenius S, Nicotera P (1996) Calcineurin and mitochondrial function in glutamate-induced neuronal cell death. FEBS Lett 394(3):321–324PubMedGoogle Scholar
  89. 89.
    Springer JE, Azbill RD, Nottingham SA, Kennedy SE (2000) Calcineurin-mediated BAD dephosphorylation activates the caspase-3 apoptotic cascade in traumatic spinal cord injury. J Neurosci 20(19):7246–7251PubMedGoogle Scholar
  90. 90.
    Saeki M, Irie Y, Ni L, Itsuki Y, Terao Y, Kawabata S, Kamisaki Y (2007) Calcineurin potentiates the activation of procaspase-3 by accelerating its proteolytic maturation. J Biol Chem 282(16):11786–11794PubMedGoogle Scholar
  91. 91.
    Ermak G, Cheadle C, Becker KG, Harris CD, Davies KJ (2004) DSCR1(Adapt78) modulates expression of SOD1. FASEB J 18(1):62–69PubMedGoogle Scholar
  92. 92.
    Silveira HC, Sommer CA, Soares-Costa A, Henrique-Silva F (2004) A calcineurin inhibitory protein overexpressed in Down's syndrome interacts with the product of a ubiquitously expressed transcript. Braz J Med Biol Res 37(6):785–789PubMedGoogle Scholar
  93. 93.
    Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS (2000) Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res 87(12):E61–E68PubMedGoogle Scholar
  94. 94.
    Lange AW, Molkentin JD, Yutzey KE (2004) DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice. Dev Biol 266(2):346–360PubMedGoogle Scholar
  95. 95.
    Hesser BA, Liang XH, Camenisch G, Yang S, Lewin DA, Scheller R, Ferrara N, Gerber HP (2004) Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood 104(1):149–158PubMedGoogle Scholar
  96. 96.
    Cano E, Canellada A, Minami T, Iglesias T, Redondo JM (2005) Depolarization of neural cells induces transcription of the Down syndrome critical region 1 isoform 4 via a calcineurin/nuclear factor of activated T cells-dependent pathway. J Biol Chem 280(33):29435–29443PubMedGoogle Scholar
  97. 97.
    Wu H, Kao SC, Barrientos T, Baldwin SH, Olson EN, Crabtree GR, Zhou B, Chang CP (2007) Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development. J Biol Chem 282(42):30673–30679PubMedCentralPubMedGoogle Scholar
  98. 98.
    Canellada A, Ramirez BG, Minami T, Redondo JM, Cano E (2008) Calcium/calcineurin signaling in primary cortical astrocyte cultures: Rcan1-4 and cyclooxygenase-2 as NFAT target genes. Glia 56(7):709–722PubMedGoogle Scholar
  99. 99.
    Bala K, Bosco R, Gramolelli S, Haas DA, Kati S, Pietrek M, Havemeier A, Yakushko Y, Singh VV, Dittrich-Breiholz O, Kracht M, Schulz TF (2012) Kaposi's sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCgamma1 and activating NFAT1-dependent RCAN1 expression. PLoS Pathog 8(9):e1002927PubMedCentralPubMedGoogle Scholar
  100. 100.
    Yao YG, Duh EJ (2004) VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis? Biochem Biophys Res Commun 321(3):648–656PubMedGoogle Scholar
  101. 101.
    Belmont PJ, Tadimalla A, Chen WJ, Martindale JJ, Thuerauf DJ, Marcinko M, Gude N, Sussman MA, Glembotski CC (2008) Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene. J Biol Chem 283(20):14012–14021PubMedCentralPubMedGoogle Scholar
  102. 102.
    Zhao P, Xiao X, Kim AS, Leite MF, Xu J, Zhu X, Ren J, Li J (2008) c-Jun inhibits thapsigargin-induced ER stress through up-regulation of DSCR1/Adapt78. Exp Biol Med (Maywood) 233(10):1289–1300Google Scholar
  103. 103.
    Oh M, Dey A, Gerard RD, Hill JA, Rothermel BA (2010) The CCAAT/enhancer binding protein beta (C/EBPβ) cooperates with NFAT to control expression of the calcineurin regulatory protein RCAN1-4. J Biol Chem 285(22):16623–16631Google Scholar
  104. 104.
    Qin L, Zhao D, Liu X, Nagy JA, Hoang MV, Brown LF, Dvorak HF, Zeng H (2006) Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol Cancer Res 4(11):811–820PubMedGoogle Scholar
  105. 105.
    Liu X, Zhao D, Qin L, Li J, Zeng H (2008) Transcription enhancer factor 3 (TEF3) mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1 L) in endothelial cells. J Biol Chem 283(49):34159–34167Google Scholar
  106. 106.
    Yoshida NL, Miyashita T, U M, Yamada M, Reed JC, Sugita Y, Oshida T (2002) Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays. Biochem Biophys Res Commun 293 (4):1254–1261Google Scholar
  107. 107.
    U M, Shen L, Oshida T, Miyauchi J, Yamada M, Miyashita T (2004) Identification of novel direct transcriptional targets of glucocorticoid receptor. Leukemia 18 (11):1850–1856Google Scholar
  108. 108.
    Liu H, Wang P, Song W, Sun X (2009) Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. FASEB J 23(10):3383–3392PubMedGoogle Scholar
  109. 109.
    Seo SR, Chung KC (2008) CREB activates proteasomal degradation of DSCR1/RCAN1. FEBS Lett 582(13):1889–1893PubMedGoogle Scholar
  110. 110.
    Lee JW, Kang HS, Lee JY, Lee EJ, Rhim H, Yoon JH, Seo SR, Chung KC (2012) The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7. Biochem Biophys Res Commun 420(2):404–410Google Scholar
  111. 111.
    Noh EH, Hwang HS, Min B, Im E, Chung KC (2012) Covalent NEDD8 conjugation increases RCAN1 protein stability and potentiates its inhibitory action on calcineurin. PLoS One 7(10):e48315PubMedCentralPubMedGoogle Scholar
  112. 112.
    Masugi F, Ogihara T, Sakaguchi K, Otsuka A, Tsuchiya Y, Morimoto S, Kumahara Y, Saeki S, Nishide M (1989) High plasma levels of cortisol in patients with senile dementia of the Alzheimer's type. Methods Find Exp Clin Pharmacol 11(11):707–710PubMedGoogle Scholar
  113. 113.
    Arsenault-Lapierre G, Chertkow H, Lupien S (2010) Seasonal effects on cortisol secretion in normal aging, mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 31(6):1051–1054PubMedGoogle Scholar
  114. 114.
    Catania C, Sotiropoulos I, Silva R, Onofri C, Breen KC, Sousa N, Almeida OF (2009) The amyloidogenic potential and behavioral correlates of stress. Mol Psychiatry 14(1):95–105PubMedGoogle Scholar
  115. 115.
    de Leon MJ, McRae T, Tsai JR, George AE, Marcus DL, Freedman M, Wolf AP, McEwen B (1988) Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy. Lancet 2(8607):391–392PubMedGoogle Scholar
  116. 116.
    Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM (2006) Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci 26(35):9047–9056Google Scholar
  117. 117.
    Laske C, Stransky E, Fritsche A, Eschweiler GW, Leyhe T (2009) Inverse association of cortisol serum levels with T-tau, P-tau 181 and P-tau 231 peptide levels and T-tau/Abeta 1–42 ratios in CSF in patients with mild Alzheimer's disease dementia. Eur Arch Psychiatry Clin Neurosci 259(2):80–85Google Scholar
  118. 118.
    Badia MC, Lloret A, Giraldo E, Dasi F, Olaso G, Alonso MD, Vina J (2013) Lymphocytes from young healthy persons carrying the ApoE4 allele overexpress stress-related proteins involved in the pathophysiology of Alzheimer's disease. J Alzheimers Dis 33(1):77–83Google Scholar
  119. 119.
    Cho KO, Kim YS, Cho YJ, Kim SY (2008) Upregulation of DSCR1 (RCAN1 or Adapt78) in the peri-infarct cortex after experimental stroke. Exp Neurol 212(1):85–92Google Scholar
  120. 120.
    Sobrado M, Ramirez BG, Neria F, Lizasoain I, Arbones ML, Minami T, Redondo JM, Moro MA, Cano E (2012) Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury. J Neuroinflammation 9:48PubMedCentralPubMedGoogle Scholar
  121. 121.
    Mines MA, Beurel E, Jope RS (2011) Regulation of cell survival mechanisms in Alzheimer's disease by glycogen synthase kinase-3. Int J Alzheimers Dis 2011:861072. doi: 10.4061/2011/861072 PubMedCentralPubMedGoogle Scholar
  122. 122.
    Reese LC, Taglialatela G (2011) A role for calcineurin in Alzheimer's disease. Curr Neuropharmacol 9(4):685–692PubMedCentralPubMedGoogle Scholar
  123. 123.
    Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF (1999) Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol 58(9):1010–1019PubMedGoogle Scholar
  124. 124.
    Asada S, Ikeda A, Nagao R, Hama H, Sudo T, Fukamizu A, Kasuya Y, Kishi T (2008) Oxidative stress-induced ubiquitination of RCAN1 mediated by SCFbeta-TrCP ubiquitin ligase. Int J Mol Med 22(1):95–104PubMedGoogle Scholar
  125. 125.
    Ihara Y, Morishima-Kawashima M, Nixon R (2012) The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease. Cold Spring Harbor Perspect Med 2(8). doi:doi: 10.1101/cshperspect.a006361
  126. 126.
    Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A 105(17):6415–6420PubMedCentralPubMedGoogle Scholar
  127. 127.
    Wang WX, Wilfred BR, Madathil SK, Tang G, Hu Y, Dimayuga J, Stromberg AJ, Huang Q, Saatman KE, Nelson PT (2010) miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am J Pathol 177(1):334–345Google Scholar
  128. 128.
    Nelson PT, Wang WX (2010) MiR-107 is reduced in Alzheimer's disease brain neocortex: validation study. J Alzheimers Dis 21(1):75–79PubMedCentralPubMedGoogle Scholar
  129. 129.
    Schonrock N, Matamales M, Ittner LM, Gotz J (2012) MicroRNA networks surrounding APP and amyloid-beta metabolism—implications for Alzheimer's disease. Exp Neurol 235(2):447–454PubMedGoogle Scholar
  130. 130.
    Lin KG, Tang M, Guo YB, Han HY, Lin YH (2011) Two polymorphisms of RCAN1 gene associated with Alzheimer's disease in the Chinese Han population. East Asian Arch Psychiatry 21(2):79–84PubMedGoogle Scholar
  131. 131.
    Uniacke J, Holterman CE, Lachance G, Franovic A, Jacob MD, Fabian MR, Payette J, Holcik M, Pause A, Lee S (2012) An oxygen-regulated switch in the protein synthesis machinery. Nature 486(7401):126–129PubMedGoogle Scholar
  132. 132.
    Janson J, Laedtke T, Parisi JE, O'Brien P, Petersen RC, Butler PC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53(2):474–481PubMedGoogle Scholar
  133. 133.
    Gao C, Holscher C, Liu Y, Li L (2012) GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease. Rev Neurosci 23(1):1–11Google Scholar
  134. 134.
    Devi L, Alldred MJ, Ginsberg SD, Ohno M (2012) Mechanisms underlying insulin deficiency-induced acceleration of beta-amyloidosis in a mouse model of Alzheimer's disease. PLoS One 7(3):e32792PubMedCentralPubMedGoogle Scholar
  135. 135.
    Peiris H, Raghupathi R, Jessup CF, Zanin MP, Mohanasundaram D, Mackenzie KD, Chataway T, Clarke JN, Brealey J, Coates PT, Pritchard MA, Keating DJ (2012) Increased expression of the glucose-responsive gene, RCAN1, causes hypoinsulinemia, ß-cell dysfunction, and diabetes. Endocrinology 153(11):5212–5221Google Scholar
  136. 136.
    Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 61(5):661–666PubMedGoogle Scholar
  137. 137.
    Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR (2006) Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199(2):265–273PubMedGoogle Scholar
  138. 138.
    Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD (2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 6(4):246–254PubMedGoogle Scholar
  139. 139.
    Head E, Lott IT, Patterson D, Doran E, Haier RJ (2007) Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention. J Alzheimers Dis 11(1):61–76PubMedGoogle Scholar
  140. 140.
    Brait VH, Martin KR, Corlett A, Broughton BR, Kim HA, Thundyil J, Drummond GR, Arumugam TV, Pritchard MA, Sobey CG (2012) Over-expression of DSCR1 protects against post-ischemic neuronal injury. PLoS One 7(10):e47841PubMedCentralPubMedGoogle Scholar
  141. 141.
    Keating DJ, Dubach D, Zanin MP, Yu Y, Martin K, Zhao YF, Chen C, Porta S, Arbones ML, Mittaz L, Pritchard MA (2008) DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: implications for Down syndrome and Alzheimer's disease. Hum Mol Genet 17(7):1020–1030PubMedGoogle Scholar
  142. 142.
    Poppek D, Keck S, Ermak G, Jung T, Stolzing A, Ullrich O, Davies KJ, Grune T (2006) Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress. Biochem J 400(3):511–520PubMedCentralPubMedGoogle Scholar
  143. 143.
    Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S, Uchida T, Imahori K (1993) Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 325(3):167–172PubMedGoogle Scholar
  144. 144.
    Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M, Ishiguro K, Yamaguchi H (1998) Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25–35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res 31(4):317–323PubMedGoogle Scholar
  145. 145.
    Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W (2008) Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med 205(12):2781–2789PubMedCentralPubMedGoogle Scholar
  146. 146.
    Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423(6938):435–439PubMedGoogle Scholar
  147. 147.
    Drewes G, Mandelkow EM, Baumann K, Goris J, Merlevede W, Mandelkow E (1993) Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcineurin and phosphatase-2A. FEBS Lett 336(3):425–432PubMedGoogle Scholar
  148. 148.
    Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1994) Alzheimer's disease abnormally phosphorylated tau is dephosphorylated by protein phosphatase-2B (calcineurin). J Neurochem 62(2):803–806PubMedGoogle Scholar
  149. 149.
    Luo J, Ma J, Yu DY, Bu F, Zhang W, Tu LH, Wei Q (2008) Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain. Brain Res Bull 76(5):464–468PubMedGoogle Scholar
  150. 150.
    Yamamoto H, Hasegawa M, Ono T, Tashima K, Ihara Y, Miyamoto E (1995) Dephosphorylation of fetal-tau and paired helical filaments-tau by protein phosphatases 1 and 2A and calcineurin. J Biochem 118(6):1224–1231PubMedGoogle Scholar
  151. 151.
    Yu DY, Tong L, Song GJ, Lin WL, Zhang LQ, Bai W, Gong H, Yin YX, Wei Q (2008) Tau binds both subunits of calcineurin, and binding is impaired by calmodulin. Biochim Biophys Acta 1783(12):2255–2261PubMedGoogle Scholar
  152. 152.
    Chang KT, Min KT (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(40):17117–17122PubMedCentralPubMedGoogle Scholar
  153. 153.
    Sun T, Wu XS, Xu J, McNeil BD, Pang ZP, Yang W, Bai L, Qadri S, Molkentin JD, Yue DT, Wu LG (2010) The role of calcium/calmodulin-activated calcineurin in rapid and slow endocytosis at central synapses. J Neurosci 30(35):11838–11847PubMedCentralPubMedGoogle Scholar
  154. 154.
    Bodmer D, Ascano M, Kuruvilla R (2011) Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth. Neuron 70(6):1085–1099PubMedCentralPubMedGoogle Scholar
  155. 155.
    Song HO, Ahnn J (2011) Calcineurin may regulate multiple endocytic processes in C. elegans. BMB Rep 44(2):96–101Google Scholar
  156. 156.
    Xue J, Graham ME, Novelle AE, Sue N, Gray N, McNiven MA, Smillie KJ, Cousin MA, Robinson PJ (2011) Calcineurin selectively docks with the dynamin Ixb splice variant to regulate activity-dependent bulk endocytosis. J Biol Chem 286(35):30295–30303PubMedCentralPubMedGoogle Scholar
  157. 157.
    Zanin MP, Mackenzie KD, Peiris H, Pritchard MA, Keating DJ (2013) RCAN1 regulates vesicle recycling and quantal release kinetics via effects on calcineurin activity. J Neurochem 124(3):290–299PubMedGoogle Scholar
  158. 158.
    Wang W, Zhu JZ, Chang KT, Min KT (2012) DSCR1 interacts with FMRP and is required for spine morphogenesis and local protein synthesis. EMBO J 31(18):3655–3666PubMedCentralPubMedGoogle Scholar
  159. 159.
    Ly PTT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W (2012) Regulation of BACE1 expression and APP processing by GSK3β signaling and its therapeutic effect on Alzheimer's disease. J Clin Invest 123(1):224–235PubMedCentralPubMedGoogle Scholar
  160. 160.
    Aplin AE, Gibb GM, Jacobsen JS, Gallo JM, Anderton BH (1996) In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta. J Neurochem 67(2):699–707PubMedGoogle Scholar
  161. 161.
    Lee MS, Kao SC, Lemere CA, Xia W, Tseng HC, Zhou Y, Neve R, Ahlijanian MK, Tsai LH (2003) APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol 163(1):83–95PubMedCentralPubMedGoogle Scholar
  162. 162.
    Kim Y, Lee YI, Seo M, Kim SY, Lee JE, Youn HD, Kim YS, Juhnn YS (2009) Calcineurin dephosphorylates glycogen synthase kinase-3 beta at serine-9 in neuroblast-derived cells. J Neurochem 111(2):344–354PubMedGoogle Scholar
  163. 163.
    Cho HJ, Jin SM, Youn HD, Huh K, Mook-Jung I (2008) Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling. Aging Cell 7(2):137–147PubMedGoogle Scholar
  164. 164.
    Ermak G, Hench KJ, Chang KT, Sachdev S, Davies KJ (2009) Regulator of calcineurin (RCAN1-1 L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro. J Biol Chem 284(18):11845–11853PubMedCentralPubMedGoogle Scholar
  165. 165.
    Kim YS, Lee HJ, Jang C, Kim HS, Cho YJ (2009) Knockdown of RCAN1.4 Increases Susceptibility to FAS-mediated and DNA-damage-induced apoptosis by upregulation of p53 expression. Korean J Physiol Pharmacol 13(6):483–489PubMedCentralPubMedGoogle Scholar
  166. 166.
    Bhoiwala DL, Koleilat I, Qian J, Beyer B, Hushmendy SF, Mathew A, Ferland RJ, Crawford DR (2013) Overexpression of RCAN1 isoform 4 in mouse neurons leads to a moderate behavioral impairment. Neurol Res 35(1):79–89PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in NeuroscienceThe University of British ColumbiaVancouverCanada
  2. 2.Ministry of Education Key Laboratory of Child Development and Disorders, and Chongqing City Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqingChina

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