Advertisement

Cellular and Molecular Life Sciences

, Volume 66, Issue 20, pp 3235–3240 | Cite as

Function and regulation of Dyrk1A: towards understanding Down syndrome

  • Joongkyu Park
  • Woo-Joo SongEmail author
  • Kwang Chul ChungEmail author
Visions & Reflections (Minireview)

Abstract

Down syndrome (DS) is associated with a variety of symptoms, such as incapacitating mental retardation and neurodegeneration (i.e., Alzheimer’s disease), that prevent patients from leading fully independent lives. These phenotypes are a direct consequence of the overexpression of chromosome 21 genes, which are present in duplicate due to non-disjunction of chromosome 21. Accumulating data suggest that the chromosome 21 gene product, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (Dyrk1A), participates in the pathogenic mechanisms underlying the mental and other physical symptoms of DS. In this review, we summarize the evidence supporting a role for Dyrk1A in DS, especially DS pathogenesis. Recently, several natural and synthetic compounds have been identified as Dyrk1A inhibitors. Understanding the function and regulation of Dyrk1A may lead to the development of novel therapeutic agents aimed at treating DS.

Keywords

Down syndrome Dyrk1A Kinase Phosphorylation Inhibitor 

Notes

Acknowledgments

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grants (R01-2007-000-11910-0 to W.-J.S. and R11-2007-040-01005-0 to K.C.C.) funded by the Ministry of Education, Science and Technology (MEST), a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2008-314-E00180 to W.-J.S.), and the Korea Health 21 R&D Project (A080551 to K.C.C.) funded by the Ministry of Health, Welfare and Family Affairs. This work was also partly supported by KOSEF grant through the National Research Laboratory Program (R04-2007-000-20014-0 to K.C.C.).

References

  1. 1.
    Lejeune J, Gautier M, Turpin R (1959) Study of somatic chromosomes from 9 mongoloid children. C R Hebd Seances Acad Sci 248:1721–1722PubMedGoogle Scholar
  2. 2.
    Korenberg JR, Chen X-N, Schipper R, Sun Z, Gonsky R, Gerwehr S, Carpenter N, Daumer C, Dignan P, Disteche C, Graham JM Jr, Hugdins L, McGillivray B, Miyazaki K, Ogasawara N, Park JP, Pagon R, Pueschel S, Sack G, Say B, Schuffenhauer S, Soukup S, Yamanaka T (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc Natl Acad Sci USA 91:4997–5001PubMedCrossRefGoogle Scholar
  3. 3.
    Gardiner K (2007) Overview of the genes of the human chromosome 21. In: Pritchard M, Reeves RH, Dierssenc M, Patterson D, Gardiner KJ (eds) Down syndrome and the genes of human chromosome 21: current knowledge and future potentials. Report on the expert workshop on the biology of chromosome 21 genes: towards gene-phenotype correlations in Down syndrome. September 28-October 1, 2007, Washington D.C. Google Scholar
  4. 4.
    Korenberg JR, Kawashima H, Pulst S-M, Ikeuchi T, Ogasawara N, Yamamoto K, Schonberg SA, West R, Allen L, Magenis E, Ikawa K, Taniguchi N, Epstein CJ (1990) Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet 47:236–246PubMedGoogle Scholar
  5. 5.
    McCormick MK, Schinzel A, Petersen MB, Stetten G, Driscoll DJ, Cantu ES, Tranebjaerg L, Mikkelsen M, Watkins PC, Antonarakis SE (1989) Molecular genetic approach to the characterization of the “Down syndrome region” of chromosome 21. Genomics 5:325–331PubMedCrossRefGoogle Scholar
  6. 6.
    Rahmani Z, Blouin J-L, Creau-Goldberg N, Watkins PC, Mattei J-F, Poissonnier M, Prieur M, Chettouh Z, Nicole A, Aurias A, Sinet P-M, Delabar J-M (1989) Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome. Proc Natl Acad Sci USA 86:5958–5962PubMedCrossRefGoogle Scholar
  7. 7.
    Ahn K-J, Jeong HK, Choi H-S, Ryoo S-R, Kim YJ, Goo J-S, Choi S-Y, Han J-S, Ha I, Song W-J (2006) DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiol Dis 22:463–472PubMedCrossRefGoogle Scholar
  8. 8.
    Altafaj X, Dierssen M, Baamonde C, Marti E, Visa J, Guimera J, Oset M, Gonzalez JR, Florez J, Fillat C, Estivill X (2001) Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down’s syndrome. Hum Mol Genet 10:1915–1923PubMedCrossRefGoogle Scholar
  9. 9.
    Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, Watabe AM, O’Dell TJ, Fung J, Weier HU, Cheng JF, Rubin EM (1997) Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nat Genet 16:28–36PubMedCrossRefGoogle Scholar
  10. 10.
    Burger PC, Vogel FS (1973) The development of the pathologic changes of Alzheimer’s disease and senile dementia in patients with Down’s syndrome. Am J Pathol 73:457–476PubMedGoogle Scholar
  11. 11.
    Olson MI, Shaw CM (1969) Presenile dementia and Alzheimer’s disease in mongolism. Brain 92:147–156PubMedCrossRefGoogle Scholar
  12. 12.
    Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17:278–282PubMedCrossRefGoogle Scholar
  13. 13.
    Kang JE, Choi SA, Park JB, Chung KC (2005) Regulation of the proapoptotic activity of huntingtin interacting protein 1 by Dyrk1 and caspase-3 in hippocampal neuroprogenitor cells. J Neurosci Res 81:62–72PubMedCrossRefGoogle Scholar
  14. 14.
    Kim EJ, Sung JY, Lee HJ, Rhim H, Hasegawa M, Iwatsubo T, Min DS, Kim J, Paik SR, Chung KC (2006) Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. J Biol Chem 281:33250–33257PubMedCrossRefGoogle Scholar
  15. 15.
    Sitz JH, Baumgartel K, Hammerle B, Papadopoulos C, Hekerman P, Tejedor FJ, Becker W, Lutz B (2008) The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4. Neuroscience 157:596–605PubMedCrossRefGoogle Scholar
  16. 16.
    Tejedor F, Zhu XR, Kaltenbach E, Ackermann A, Baumann A, Canal I, Heisenberg M, Fischbach KF, Pongs O (1995) Minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron 14:287–301PubMedCrossRefGoogle Scholar
  17. 17.
    Guimera J, Casas C, Pucharcos C, Solans A, Domenech A, Planas AM, Ashley J, Lovett M, Estivill X, Pritchard MA (1996) A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. Hum Mol Genet 5:1305–1310PubMedCrossRefGoogle Scholar
  18. 18.
    Kentrup H, Becker W, Heukelbach J, Wilmes A, Schurmann A, Huppertz C, Kainulainen H, Joost HG (1996) Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII. J Biol Chem 271:3488–3495PubMedCrossRefGoogle Scholar
  19. 19.
    Song W-J, Sternberg LR, Kasten-Sportes C, Keuren ML, Chung S-H, Slack AC, Miller DE, Glover TW, Chiang P-W, Lou L, Kurnit DM (1996) Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome “critical region”. Genomics 38:331–339PubMedCrossRefGoogle Scholar
  20. 20.
    Becker W, Joost HG (1999) Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity. Prog Nucleic Acid Res Mol Biol 62:1–17PubMedCrossRefGoogle Scholar
  21. 21.
    Lochhead PA, Sibbet G, Morrice N, Cleghon V (2005) Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell 121:925–936PubMedCrossRefGoogle Scholar
  22. 22.
    Alvarez M, Estivill X, de la Luna S (2003) DYRK1A accumulates in splicing speckles through a novel targeting signal and induces speckle disassembly. J Cell Sci 116:3099–3107PubMedCrossRefGoogle Scholar
  23. 23.
    Hammerle B, Elizalde C, Tejedor FJ (2008) The spatio-temporal and subcellular expression of the candidate Down syndrome gene Mnb/Dyrk1A in the developing mouse brain suggests distinct sequential roles in neuronal development. Eur J Neurosci 27:1061–1074PubMedCrossRefGoogle Scholar
  24. 24.
    Galceran J, de Graaf K, Tejedor FJ, Becker W (2003) The MNB/DYRK1A protein kinase: genetic and biochemical properties. J Neural Transm Suppl 67:139–148PubMedGoogle Scholar
  25. 25.
    Hammerle B, Elizalde C, Galceran J, Becker W, Tejedor FJ (2003) The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications. J Neural Transm Suppl 67:129–137PubMedGoogle Scholar
  26. 26.
    Skurat AV, Dietrich AD (2004) Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J Biol Chem 279:2490–2498PubMedCrossRefGoogle Scholar
  27. 27.
    Laguna A, Aranda S, Barallobre MJ, Barhoum R, Fernandez E, Fotaki V, Delabar JM, de la Luna S, de la Villa P, Arbones ML (2008) The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development. Dev Cell 15:841–853PubMedCrossRefGoogle Scholar
  28. 28.
    Fernandez-Martinez J, Vela EM, Tora-Ponsioen M, Ocana OH, Nieto MA, Galceran J (2009) Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A. J Cell Sci 122:1574–1583PubMedCrossRefGoogle Scholar
  29. 29.
    Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441:595–600PubMedCrossRefGoogle Scholar
  30. 30.
    Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A (2006) A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441:646–650PubMedCrossRefGoogle Scholar
  31. 31.
    Guimera J, Casas C, Estivill X, Pritchard M (1999) Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome. Genomics 57:407–418PubMedCrossRefGoogle Scholar
  32. 32.
    Dowjat WK, Adayev T, Kuchna I, Nowicki K, Palminiello S, Hwang YW, Wegiel J (2007) Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome. Neurosci Lett 413:77–81PubMedCrossRefGoogle Scholar
  33. 33.
    Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, Kazui H, Hashimoto R, Tanaka T, Kudo T, Yamagata H, Tabara Y, Miki T, Akatsu H, Kosaka K, Funakoshi E, Nishitomi K, Sakaguchi G, Kato A, Hattori H, Uema T, Takeda M (2007) The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet 16:15–23PubMedCrossRefGoogle Scholar
  34. 34.
    Maenz B, Hekerman P, Vela EM, Galceran J, Becker W (2008) Characterization of the human DYRK1A promoter and its regulation by the transcription factor E2F1. BMC Mol Biol 9:30PubMedCrossRefGoogle Scholar
  35. 35.
    Kim MY, Jeong BC, Lee JH, Kee HJ, Kook H, Kim NS, Kim YH, Kim JK, Ahn KY, Kim KK (2006) A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci USA 103:13074–13079PubMedCrossRefGoogle Scholar
  36. 36.
    Kim D, Won J, Shin DW, Kang J, Kim YJ, Choi SY, Hwang M-K, Jeong B-W, Kim GS, Joe CO, Chung S-H, Song W-J (2004) Regulation of Dyrk1A kinase activity by 14-3-3. Biochem Biophys Res Commun 323:499–504PubMedCrossRefGoogle Scholar
  37. 37.
    Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, Schmidt C, Bronson RT, Davisson MT (1995) A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet 11:177–184PubMedCrossRefGoogle Scholar
  38. 38.
    Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, Epstein CJ, Huang TT (1998) Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc Natl Acad Sci USA 95:6256–6261PubMedCrossRefGoogle Scholar
  39. 39.
    Siarey RJ, Stoll J, Rapoport SI, Galdzicki Z (1997) Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome. Neuropharmacology 36:1549–1554PubMedCrossRefGoogle Scholar
  40. 40.
    Siarey RJ, Villar AJ, Epstein CJ, Galdzicki Z (2005) Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome. Neuropharmacology 49:122–128PubMedCrossRefGoogle Scholar
  41. 41.
    Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ, Salehi A, Mobley WC (2004) Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. J Comp Neurol 480:281–298PubMedCrossRefGoogle Scholar
  42. 42.
    Belichenko PV, Kleschevnikov AM, Salehi A, Epstein CJ, Mobley WC (2007) Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol 504:329–345PubMedCrossRefGoogle Scholar
  43. 43.
    Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC (2009) The “Down syndrome critical region” is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci 29:5938–5948PubMedCrossRefGoogle Scholar
  44. 44.
    Olson LE, Roper RJ, Sengstaken CL, Peterson EA, Aquino V, Galdzicki Z, Siarey R, Pletnikov M, Moran TH, Reeves RH (2007) Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice. Hum Mol Genet 16:774–782PubMedCrossRefGoogle Scholar
  45. 45.
    Benavides-Piccione R, Dierssen M, Ballesteros-Yanez I, Martinez de Lagran M, Arbones ML, Fotaki V, DeFelipe J, Elston GN (2005) Alterations in the phenotype of neocortical pyramidal cells in the Dyrk1A+/– mouse. Neurobiol Dis 20:115–122PubMedCrossRefGoogle Scholar
  46. 46.
    Fotaki V, Dierssen M, Alcantara S, Martinez S, Marti E, Casas C, Visa J, Soriano E, Estivill X, Arbones ML (2002) Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol Cell Biol 22:6636–6647PubMedCrossRefGoogle Scholar
  47. 47.
    Moller RS, Kubart S, Hoeltzenbein M, Heye B, Vogel I, Hansen CP, Menzel C, Ullmann R, Tommerup N, Ropers HH, Tumer Z, Kalscheuer VM (2008) Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am J Hum Genet 82:1165–1170PubMedCrossRefGoogle Scholar
  48. 48.
    Hanger DP, Brion JP, Gallo JM, Cairns NJ, Luthert PJ, Anderton BH (1991) Tau in Alzheimer’s disease and Down’s syndrome is insoluble and abnormally phosphorylated. Biochem J 275(Pt 1):99–104PubMedGoogle Scholar
  49. 49.
    Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249PubMedCrossRefGoogle Scholar
  50. 50.
    Park J, Yang EJ, Yoon JH, Chung KC (2007) Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome. Mol Cell Neurosci 36:270–279PubMedCrossRefGoogle Scholar
  51. 51.
    Ryoo S-R, Cho H-J, Lee H-W, Jeong HK, Radnaabazar C, Kim Y-S, Kim M-J, Son M-Y, Seo H, Chung S-H, Song W-J (2008) Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease. J Neurochem 104:1333–1344PubMedCrossRefGoogle Scholar
  52. 52.
    Ferrer I, Barrachina M, Puig B, Martinez de Lagran M, Marti E, Avila J, Dierssen M (2005) Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models. Neurobiol Dis 20:392–400PubMedCrossRefGoogle Scholar
  53. 53.
    Ryoo S-R, Jeong HK, Radnaabazar C, Yoo J-J, Cho H-J, Lee H-W, Kim I-S, Cheon Y-H, Ahn YS, Chung S-H, Song W-J (2007) DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease. J Biol Chem 282:34850–34857PubMedCrossRefGoogle Scholar
  54. 54.
    Wegiel J, Dowjat K, Kaczmarski W, Kuchna I, Nowicki K, Frackowiak J, Mazur Kolecka B, Wegiel J, Silverman WP, Reisberg B, Deleon M, Wisniewski T, Gong CX, Liu F, Adayev T, Chen-Hwang MC, Hwang YW (2008) The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome. Acta Neuropathol 116:391–407PubMedCrossRefGoogle Scholar
  55. 55.
    Patterson D (1987) The causes of Down syndrome. Sci Am 257:52–57, 60Google Scholar
  56. 56.
    Pulsifer MB (1996) The neuropsychology of mental retardation. J Int Neuropsychol Soc 2:159–176PubMedCrossRefGoogle Scholar
  57. 57.
    Mann DM, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 89:169–179PubMedCrossRefGoogle Scholar
  58. 58.
    Bianchetti A, Trabucchi M, Cipriani G (2003) Aggressive behaviour associated with donepezil treatment: a case report. Int J Geriatr Psychiatry 18:657–658PubMedCrossRefGoogle Scholar
  59. 59.
    Lott IT, Osann K, Doran E, Nelson L (2002) Down syndrome and Alzheimer disease: response to donepezil. Arch Neurol 59:1133–1136PubMedCrossRefGoogle Scholar
  60. 60.
    Lobaugh NJ, Karaskov V, Rombough V, Rovet J, Bryson S, Greenbaum R, Haslam RH, Koren G (2001) Piracetam therapy does not enhance cognitive functioning in children with down syndrome. Arch Pediatr Adolesc Med 155:442–448PubMedGoogle Scholar
  61. 61.
    Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC (2007) Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci 10:411–413PubMedGoogle Scholar
  62. 62.
    Costa AC, Scott-McKean JJ, Stasko MR (2008) Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology 33:1624–1632PubMedCrossRefGoogle Scholar
  63. 63.
    Guedj F, Sebrie C, Rivals I, Ledru A, Paly E, Bizot JC, Smith D, Rubin E, Gillet B, Arbones M, Delabar JM (2009) Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS ONE 4:e4606PubMedCrossRefGoogle Scholar
  64. 64.
    Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408:297–315PubMedCrossRefGoogle Scholar
  65. 65.
    Ortiz-Abalia J, Sahun I, Altafaj X, Andreu N, Estivill X, Dierssen M, Fillat C (2008) Targeting Dyrk1A with AAVshRNA attenuates motor alterations in TgDyrk1A, a mouse model of Down syndrome. Am J Hum Genet 83:479–488PubMedCrossRefGoogle Scholar
  66. 66.
    Kim ND, Yoon J, Kim JH, Lee JT, Chon YS, Hwang M-K, Ha I, Song W-J (2006) Putative therapeutic agents for the learning and memory deficits of people with Down syndrome. Bioorg Med Chem Lett 16:3772–3776PubMedCrossRefGoogle Scholar
  67. 67.
    Koo KA, Kim ND, Chon YS, Jung M-S, Lee B-J, Kim JH, Song W-J (2009) QSAR analysis of pyrazolidine-3,5-diones derivatives as Dyrk1A inhibitors. Bioorg Med Chem Lett 19:2324–2328PubMedCrossRefGoogle Scholar
  68. 68.
    Kuhn C, Frank D, Will R, Jaschinski C, Frauen R, Katus HA, Frey N (2009) DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy. J Biol Chem 284:17320–17327PubMedCrossRefGoogle Scholar
  69. 69.
    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 459:1126–1130PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  1. 1.Department of Biology, College of Life Science and BiotechnologyYonsei UniversitySeoulRepublic of Korea
  2. 2.Graduate Program in Neuroscience, Institute for Brain Science and Technology (IBST)Inje UniversityBusanRepublic of Korea

Personalised recommendations