Amino Acids

, Volume 45, Issue 2, pp 269–278

Nardilysin in human brain diseases: both friend and foe

  • H.-G. Bernstein
  • R. Stricker
  • H. Dobrowolny
  • J. Steiner
  • B. Bogerts
  • K. Trübner
  • G. Reiser
Minireview Article

Abstract

Nardilysin is a metalloprotease that cleaves peptides, such as dynorphin-A, α-neoendorphin, and glucagon, at the N-terminus of arginine and lysine residues in dibasic moieties. It has various functionally important molecular interaction partners (heparin-binding epidermal growth factor-like growth factor, tumour necrosis factor-α-converting enzyme, neuregulin 1, beta-secretase 1, malate dehydrogenase, P42IP4/centaurin-α1, the histone H3 dimethyl Lys4, and others) and is involved in a plethora of normal brain functions. Less is known about possible implications of nardilysin for brain diseases. This review, which includes some of our own recent findings, attempts to summarize the current knowledge on possible roles of nardilysin in Alzheimer disease, Down syndrome, schizophrenia, mood disorders, alcohol abuse, heroin addiction, and cancer. We herein show that nardilysin is a Janus-faced enzyme with regard to brain pathology, being probably neuropathogenic in some diseases, but neuroprotective in others.

Keywords

Nardilysin Alzheimer disease Schizophrenia Alcoholism Heroin addiction Brain tumour 

Abbreviations

ACC

Anterior cingulate cortex

AD

Alzheimer disease

ADAM

A disintegrin and metalloprotease

APP

Amyloid precursor protein

BACE

Beta-site APP cleaving enzyme

CNS

Central nervous system

DLP

Dorso-lateral prefrontal cortex

DS

Down syndrome

EGF

Epidermal growth factor

erbB

Epidermal growth factor receptor (tyrosine kinase)

HB-EGF

Heparin-binding epidermal growth factor-like growth factor

HXXEH

His-Xaa-Xaa-Glu-His zinc–binding motif of the inverzincin/M16 family of metalloproteases

NRDc

Nardilysin

NRG

Neuregulin

PVN

Paraventicular nucleus

PNS

Peripheral nervous system

SON

Supraoptic nucleus

SH-SY5Y

Human neuroblastoma cell line

TACE

Tumour necrosis factor-α-converting enzyme

TNF-α

Tumour necrosis factor

References

  1. Akil H, Atz M, Bunney Jr WE, Byerley W, Casey K, Choudary P, Evans SJ Jones EG, Li J, Lopez JF, Myer RM, Rollins B, Thompson RC, Tomita H, Vawter MP, Watson SJ (2006) Compositions and methods for diagnosing and treating neuropsychiatric disorders. United States Patent Application 20060257903Google Scholar
  2. Banerjee A, Macdonald ML, Borgmann-Winter KE, Hahn CG (2010) Neuregulin 1-erbB4 pathway in schizophrenia: from genes to an interactome. Brain Res Bull 83:132–139PubMedCrossRefGoogle Scholar
  3. Bataille D, Fontés G, Costes S, Longuet C, Dalle S (2006) The glucagon-miniglucagon interplay: a new level in the metabolic regulation. Ann N Y Acad Sci 1070:161–166PubMedCrossRefGoogle Scholar
  4. Bekris LM, Lutz F, Li G, Galasko DR, Farlow MR, Quinn JF, Kaye JA, Leverenz JB, Tsuang DW, Montine TJ, Peskind ER, Yu CE (2012) ADAM10 expression and promoter haplotype in Alzheimer’s disease. Neurobiol Aging 33:2229-e1–2229-e9CrossRefGoogle Scholar
  5. Bernstein HG (2005) Proteases and Alzheimer disease: Present knowledge and emerging concepts of therapy. In: Lendeckel U, Hooper NM (eds) Proteases in the Brain. Springer, New York, pp 1–23CrossRefGoogle Scholar
  6. Bernstein HG, Bukowska A, Krell D, Bogerts B, Ansorge S, Lendeckel U (2003) Comparative localization of ADAMs 10 and 15 in human cerebral cortex normal aging, Alzheimer disease and Down syndrome. J Neurocytol 32:153–160PubMedCrossRefGoogle Scholar
  7. Bernstein HG, Lendeckel U, Bertram I, Bukowska A, Kanakis D, Dobrowolny H, Stauch R, Krell D, Mawrin C, Budinger E, Keilhoff G, Bogerts B (2006) Localization of neuregulin-1alpha (heregulin-alpha) and one of its receptors, ErbB-4 tyrosine kinase, in developing and adult human brain. Brain Res Bull 69:546–559PubMedCrossRefGoogle Scholar
  8. Bernstein HG, Stricker R, Dobrowolny H, Trübner K, Bogerts B, Reiser G (2007) Histochemical evidence for wide expression of the metalloendopeptidase nardilysin in human brain neurons. Neuroscience 146:1513–1523PubMedCrossRefGoogle Scholar
  9. Bernstein HG, Stricker R, Lendeckel U, Bertram I, Dobrowolny H, Steiner J, Bogerts B, Reiser G (2009a) Reduced neuronal co-localisation of nardilysin and the putative alpha-secretases ADAM10 and ADAM17 in Alzheimer’s disease and Down syndrome brains. Age 31:11–25PubMedCrossRefGoogle Scholar
  10. Bernstein HG, Steiner J, Bogerts B (2009b) Glial cells in schizophrenia: pathophysiological significance and possible consequences for therapy. Expert Rev Neurother 9:1059–1071PubMedCrossRefGoogle Scholar
  11. Bernstein H-G, Stricker R, Bertram I, Lendeckel U, Steiner J, Bogerts B. Reiser G (2011) Nardilysin and neuregulin-1 are largely co-localised in human cortex neurons and strongly up-regulated in schizophrenia. 10th World Congress of Biological Psychiatry Prague, abstr. P 18-013Google Scholar
  12. Bernstein HG, Stricker R, Zschiebsch K, Müller S, Dobrowolny H, Steiner J, Bogerts B, Reiser G (2013) Decreased expression of nardilysin in SH-SY5Y cells under ethanol stress and reduced density of nardilysin-expressing neurons in brains of alcoholics. J Psychiatr Res 47:343–349PubMedCrossRefGoogle Scholar
  13. Bertram I, Bernstein HG, Lendeckel U, Bukowska A, Dobrowolny H, Keilhoff G, Kanakis D, Mawrin C, Bielau H, Falkai P, Bogerts B (2007) Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. Ann N Y Acad Sci 1096:147–156PubMedCrossRefGoogle Scholar
  14. Borrmann C, Stricker R, Reiser G (2011a) Retinoic acid-induced upregulation of the metalloendopeptidase nardilysin is accelerated by co-expression of the brain-specific protein p42(IP4) (centaurin α 1; ADAP1) in neuroblastoma cells. Neurochem Int 59:936–944PubMedCrossRefGoogle Scholar
  15. Borrmann C, Stricker R, Reiser G (2011b) Tubulin potentiates the interaction of the metalloendopeptidase nardilysin with the neuronal scaffold protein p42IP4/centaurin-α1 (ADAP1). Cell Tissue Res 346:89–98PubMedCrossRefGoogle Scholar
  16. Braak H, Del Tredici K (2012) Where, when, and in what form does sporadic Alzheimer’s disease begin? Curr Opin Neurol 25(6):708–714PubMedCrossRefGoogle Scholar
  17. Chang GQ, Karatayev O, Ahsan R, Avena NM, Lee C, Lewis MJ, Hoebel BG, Leibowitz SF (2007) Effect of ethanol on hypothalamic opioid peptides, enkephalin, and dynorphin: relationship with circulating triglycerides. Alcoholism Clin Exp Res 31:249–259CrossRefGoogle Scholar
  18. Chang GQ, Barson JR, Karatayev O, Chang SY, Chen YW, Leibowitz SF (2010) Effect of chronic ethanol on enkephalin in the hypothalamus and extra-hypothalamic areas. Alcohol Clin Exp Res 34:761–770PubMedCrossRefGoogle Scholar
  19. Chen CP, Kuhn P, Chaturvedi K, Boyadjieva N, Sarkar DK (2006) Ethanol induces apoptotic death of developing beta-endorphin neurons via suppression of cyclic adenosine monophosphate production and activation of transforming growth factor-beta1-linked apoptotic signalling. Mol Pharmacol 69:706–717PubMedGoogle Scholar
  20. Cheon MS, Dierssen M, Kim SH, Lubec G (2008) Protein expression of BACE1, BACE2 and APP in Down syndrome brains. Amino Acids 35:339–343PubMedCrossRefGoogle Scholar
  21. Chesneau V, Pierotti AR, Barré N, Creminon C, Tougard C, Cohen P (1994) Isolation and characterization of a dibasic selective metalloendopeptidase from rat testes that cleaves at the amino terminus of arginine residues. J Biol Chem 269:2056–2061PubMedGoogle Scholar
  22. Chow KM, Oakley O, Goodman J, Ma Z, Juliano MA, Juliano L, Hersh LB (2003) Nardilysin cleaves peptides at monobasic sites. Biochemistry 42:2239–2244PubMedCrossRefGoogle Scholar
  23. Chow KM, Ma Z, Cai J, Pierce WM, Hersh LB (2005) Nardilysin facilitates complex formation between mitochondrial malate dehydrogenase and citrate synthase. Biochim Biophys Acta 1723:292–301PubMedCrossRefGoogle Scholar
  24. Clarke TK, Ambrose-Lanci L, Ferraro TN, Berrettini WH, Kampman KM, Dackis CA, Pettinati HM, O’Brien CP, Oslin DW, Lohoff FW (2012) Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction. Genes Brain Behav 11:415–423PubMedCrossRefGoogle Scholar
  25. Coffill CR, Muller PA, Oh HK, Neo SP, Hogue KA, Cheok CF, Vousden KH, Lane DP, Blackstock WP, Gunaratne J (2012) Mutant p53 interactome identifies nardilysin as a p53R273H-specific binding partner that promotes invasion. EMBO Rep 13:638–644PubMedCrossRefGoogle Scholar
  26. Colciaghi F, Marcello E, Borroni B, Zimmermann M, Caltagirone C, Cattabeni F, Padovani A, Di Luca M (2004) Platelet APP, ADAM 10 and BACE alterations in the early stages of Alzheimer disease. Neurology 62:498–501PubMedCrossRefGoogle Scholar
  27. Connor CM, Guo Y, Akbarian S (2009) Cingulate white matter neurons in schizophrenia and bipolar disorder. Biol Psychiatry 66:486–493PubMedCrossRefGoogle Scholar
  28. Crews FT, Nixon K (2009) Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcoholism 44:115–127PubMedCrossRefGoogle Scholar
  29. Crow KE, Braggins TJ, Batt RD, Hardmann MJ (1982) Rat liver cytosolic malate dehydrogenase: purification, kinetic properties, role in control of free cytosolic NADPH concentration. Analysis of control of ethanol metabolism using computer simulation. J Biol Chem 257:14217–14225PubMedGoogle Scholar
  30. Csuhai E, Chen G, Hersh LB (1998) Regulation of N-arginine dibasic convertase activity by amines: putative role of a novel acidic domain as an amine binding site. Biochemistry 37:3787–3794PubMedCrossRefGoogle Scholar
  31. De Vries TJ, Shippenberg TS (2002) Neural systems underlying opiate addiction. J Neurosci 22:3321–3325PubMedGoogle Scholar
  32. Draoui M, Bellincampi L, Hospital V, Cadel S, Foulon T, Prat A, Barré N, Reichert U, Melino G, Cohen P (1997) Expression and retinoid modulation of N-arginine dibasic convertase and an aminopeptidase-B in human neuroblastoma cell lines. J Neurooncol 31:99–106PubMedCrossRefGoogle Scholar
  33. Endres K, Fahrenholz F (2010) Upregulation of the alpha-secretase ADAM10—risk or reason for hope? FEBS J 277:1585–1796PubMedCrossRefGoogle Scholar
  34. Endres K, Fahrenholz F (2012) Regulation of α-secretase ADAM10 expression and activity. Exp Brain Res 217:343–352PubMedCrossRefGoogle Scholar
  35. Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE (2003) Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 73:601–611PubMedCrossRefGoogle Scholar
  36. Ferriero DM, Sheldon RA, Doming J (1992) Somatostatin is altered in developing retina from ethanol-exposed rats. Neurosci Lett 147:29–32PubMedCrossRefGoogle Scholar
  37. Fontés G, Lajoix AD, Bergeron F, Cadel S, Prat A, Foulon T, Gross R, Dalle S, Le-Nguyen D, Tribillac F, Bataille D (2005) Miniglucagon (MG)-generating endopeptidase, which processes glucagon into MG, is composed of N-arginine dibasic convertase and aminopeptidase B. Endocrinology 146:702–712PubMedCrossRefGoogle Scholar
  38. Fumagalli P, Accarino M, Egeo A, Scartezzini P, Rappazzo G, Pizzuti A, Avvantaggiato V, Simeone A, Arrigo G, Zuffardi O, Ottolenghi S, Taramelli R (1998) Human NRD convertase: a highly conserved metalloendopeptidase expressed at specific sites during development and in adult tissues. Genomics 47:238–245PubMedCrossRefGoogle Scholar
  39. Gluschankof P, Morel A, Gomez S, Nicolas P, Fahy C, Cohen P (1984) Enzymes processing somatostatin precursors: an Arg-Lys esteropeptidase from the rat brain cortex converting somatostatin-28 into somatostatin-14. Proc Natl Acad Sci USA 81:6662–6666PubMedCrossRefGoogle Scholar
  40. Gough M, Parr-Sturgess C, Parkin E (2011) Zinc metalloproteinases and amyloid beta-peptide metabolism: The positive side of proteolysis in Alzheimer’s disease. Biochem Res Int Article ID 721463Google Scholar
  41. Hiraoka Y, Ohno M, Yoshida K, Okawa K, Tomimoto H, Kita T, Nishi E (2007) Enhancement of alpha-secretase cleavage of amyloid precursor protein by a metalloendopeptidase nardilysin. J Neurochem 102:1595–1605PubMedCrossRefGoogle Scholar
  42. Hooper NM (1994) Families of zinc metalloproteases. FEBS Lett 354:1–6PubMedCrossRefGoogle Scholar
  43. Hooper NM, Turner AJ (2002) The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer’s disease. Curr Med Chem 9:1107–1119PubMedCrossRefGoogle Scholar
  44. Hospital V, Prat A (2004) Nardilysin, a basic residues specific metallopeptidase that mediates cell migration and proliferation. Protein Pept Lett 11:501–508PubMedCrossRefGoogle Scholar
  45. Hospital V, Prat A, Joulie C, Chérif D, Day R, Cohen P (1997) Human and rat testis express two mRNA species encoding variants of NRD convertase, a metalloendopeptidase of the insulinase family. Biochem J 327:773–779PubMedGoogle Scholar
  46. Hospital V, Nishi E, Klagsbrun M, Cohen P, Seidah NG, Prat A (2002) The metalloendopeptidase nardilysin (NRDc) is potently inhibited by heparin-binding epidermal growth factor-like growth factor (HB-EGF). Biochem J 367:229–238PubMedCrossRefGoogle Scholar
  47. Ichimura K, Pearson DM, Kocialkowski S, Bäcklund LM, Chan R, Jones DT, Collins VP (2009) IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 11:341–347PubMedCrossRefGoogle Scholar
  48. Jin K, Mao XO, Sun Y, Xie L, Jin L, Nishi E, Klagsbrun M, Greenberg DA (2002) Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. J Neurosci 22:5365–5373PubMedGoogle Scholar
  49. Kanda K, Komekado H, Sawabu T, Ishizu S, Nakanishi Y, Nakatsuji M, Akitake-Kawano R, Ohno M, Hiraoka Y, Kawada M, Kawada K, Sakai Y, Matsumoto K, Kunichika M, Kimura T, Seno H, Nishi E, Chiba T (2012) Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF-α. EMBO Mol Med 4:396–411PubMedCrossRefGoogle Scholar
  50. Konradi C (2012) Methods for diagnosis and prognosis of psychotic disorders. US Patent 8,163,475,2012Google Scholar
  51. Law AJ, Shannon Weickert C, Hyde TM, Kleinman JE, Harrison PJ (2004) Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. Neuroscience 127:125–136PubMedCrossRefGoogle Scholar
  52. Lerner AJ, Gustaw-Rothenberg K, Smyth S, Casadesus G (2012) Retinoids for treatment of Alzheimer’s disease. BioFactors 38:84–89PubMedCrossRefGoogle Scholar
  53. Li J, Chu M, Wang S, Chan D, Qi S, Wu M, Zhou Z, Li J, Nishi E, Qin J, Wong J (2012) Identification and characterization of nardilysin as a novel dimethyl H3K4-binding protein involved in transcriptional regulation. J Biol Chem 287:10089–10098PubMedCrossRefGoogle Scholar
  54. Lichtenthaler SF (2012) Alpha-secretase cleavage of the amyloid precursor protein: proteolysis regulated by signaling pathways and protein trafficking. Curr Alzheimer Res 9:165–177PubMedCrossRefGoogle Scholar
  55. Lin A, Reniers RL, Wood SJ (2013) Clinical staging in severe mental disorder: evidence from neurocognition and neuroimaging. Br J Psychiatry 54:11–27CrossRefGoogle Scholar
  56. Ma Z, Csuhai E, Chow KM, Hersh LB (2001) Expression of the acidic stretch of nardilysin as a functional binding domain. Biochemistry 40:9447–9452PubMedCrossRefGoogle Scholar
  57. Maes OC, Xu S, Yu B, Chertkow HM, Wang E, Schipper HM (2007) Transcriptional profiling of Alzheimer blood mononuclear cells by microarray. Neurobiol Aging 28:1795–1809PubMedCrossRefGoogle Scholar
  58. Nash RJ, Heimburg-Molinaro J, Nash RJ (2009) Heparin binding epidermal growth factor-like growth factor reduces ethanol-induced apoptosis and differentiation in human embryonic stem cells. Growth Factors 27:362–369PubMedCrossRefGoogle Scholar
  59. Nishi E (2013) Nardilysin. In: Rawlings N, Salvesen G (eds) Handbook of Proteolytic Enzymes, 3rd edn. Academic Press, NewYork, pp 1421–1426Google Scholar
  60. Nishi E, Prat A, Hospital V, Elenius K, Klagsbrun M (2001) N-arginine dibasic convertase is a specific receptor for heparin-binding EGF-like growth factor that mediates cell migration. EMBO J 20:3342–3350PubMedCrossRefGoogle Scholar
  61. Nishi E, Hiraoka Y, Yoshida K, Okawa K, Kita T (2006) Nardilysin enhances ectodomain shedding of heparin-binding epidermal growth factor-like growth factor through activation of tumor necrosis factor-alpha-converting enzyme. J Biol Chem 281:31164–31172PubMedCrossRefGoogle Scholar
  62. Ohno M (2011) Nardilysin prevents amyloid plaque formation by enhancing alpha-secretase activity in vivo. Alzheimer’s Dementia J Alzheimer’s Assoc 7:S412CrossRefGoogle Scholar
  63. Ohno M, Hiraoka Y, Matsuoka T, Tomimoto H, Takao K, Miyakawa T, Oshima N, Kiyonari H, Kimura T, Kita T, Nishi E (2009) Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system. Nat Neurosci 12:1506–1513PubMedCrossRefGoogle Scholar
  64. Ono K, Yamada M (2012) Vitamin A and Alzheimer’s disease. Geriatr Gerontol Int 12:180–188PubMedCrossRefGoogle Scholar
  65. Pierotti AR, Prat A, Chesneau V, Gaudoux F, Leseney AM, Foulon T, Cohen P (1994) N-arginine dibasic convertase, a metalloendopeptidase as a prototype of a class of processing enzymes. Proc Natl Acad Sci USA 91:6078–6082PubMedCrossRefGoogle Scholar
  66. Przewłocka B, Lasoń W, Przewłocki R (1992) Repeated ethanol administration decreases prodynorphin biosynthesis in the rat hippocampus. Neurosci Lett 13:195–198CrossRefGoogle Scholar
  67. Rawlings ND, Barrett AJ (1993) Evolutionary families of peptidases. Biochem J 290:205–218PubMedGoogle Scholar
  68. Reiser G, Bernstein HG (2002) Neurons and plaques of Alzheimer’s disease patients highly express the neuronal membrane docking protein p42IP4/centaurin α. NeuroReport 13:2417–2419PubMedCrossRefGoogle Scholar
  69. Reiser G, Bernstein HG (2004) Altered expression of protein p42IP4/centaurin-α1 in Alzheimer’s disease brains and possible interaction of p42IP4 with nucleolin. NeuroReport 15:147–148PubMedCrossRefGoogle Scholar
  70. Rodd ZA, Kimpel MW, Edenberg HJ, Bell RL, Strother WN, McClintick JN, Carr LG, Liang T, McBride WJ (2008) Differential gene expression in the nucleus accumbens with ethanol self-administration in inbred alcohol-preferring rats. Pharmacol Biochem Behav 89:481–498PubMedCrossRefGoogle Scholar
  71. Seidah NG, Prat A (2002) Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem 38:79–94PubMedGoogle Scholar
  72. Stricker R, Chow KM, Walther D, Hanck T, Hersh LB, Reiser G (2006) Interaction of the brain-specific proteinp42IP4/centaurin-alpha 1 with the peptidase nardilysin is regulated by the cognate ligands of p42IP4, PtdIns (3,4,5)P3 and Ins(1,3,4,5)P4, with stereospecificity. J Neurochem 98:343–354PubMedCrossRefGoogle Scholar
  73. Sulman EP, Dumanski JP, White PS, Zhao H, Maris JM, Mathiesen T, Bruder C, Cnaan A, Brodeur GM (1998) Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity. Cancer Res 58:3226–3230PubMedGoogle Scholar
  74. Szatmari EM, Oliveira AF, Sumner EJ, Yasuda R (2013) Centaurin-α1-Ras-Elk-1 signalling at mitochondria mediates β-amyloid-induced synaptic dysfunction. J Neurosci 33:5367–5374PubMedCrossRefGoogle Scholar
  75. Vincent B, Checler F (2012) α-Secretase in Alzheimer’s disease and beyond: mechanistic, regulation and function in the shedding of membrane proteins. Curr Alzheimer Res 9:140–156PubMedCrossRefGoogle Scholar
  76. Wang XD, Su YA, Guo CM, Yang Y, Si TM (2008) Chronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus. Int J Neuropsychopharmacol 11:553–561PubMedGoogle Scholar
  77. Wang K-S, Liu X, Zhang Q, Pan Y, Aragam N, Zeng M (2011) A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence. J Psychiatr Res 45:1419–1425PubMedCrossRefGoogle Scholar
  78. Zinner SH, Batanian JR (2003) Second reported patient with del(1)(p32.1p32.3) and similar clinical features suggesting a recognizable chromosomal syndrome. Am J Med Genet 122A:64–167CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • H.-G. Bernstein
    • 1
  • R. Stricker
    • 2
  • H. Dobrowolny
    • 1
  • J. Steiner
    • 1
  • B. Bogerts
    • 1
  • K. Trübner
    • 3
  • G. Reiser
    • 2
  1. 1.Department of PsychiatryOtto-v.-Guericke University MagdeburgMagdeburgGermany
  2. 2.Institute of NeurobiochemistryOtto-v.-Guericke University MagdeburgMagdeburgGermany
  3. 3.Department of PsychiatryInstitute for Legal Medicine, University of Essen-DuisburgEssenGermany

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