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A possible pathophysiological role of tyrosine hydroxylase in Parkinson’s disease suggested by postmortem brain biochemistry: a contribution for the special 70th birthday symposium in honor of Prof. Peter Riederer

  • Movement Disorders - Review article
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Abstract

Postmortem brain biochemistry has revealed that the main symptom of movement disorder in Parkinson’s disease (PD) is caused by a deficiency in dopamine (DA) at the nerve terminals of degenerating nigro-striatal DA neurons in the striatum. Since tyrosine hydroxylase (TH) is the rate-limiting enzyme for the biosynthesis of DA, TH may play an important role in the disease process of PD. DA regulated by TH activity is thought to interact with α-synuclein protein, which results in intracellular aggregates called Lewy bodies and causes apoptotic cell death during the aging process. Human TH has several isoforms produced by alternative mRNA splicing, which may affect activation by phosphorylation of serine residues in the N-terminus of TH. The activity and protein level of TH are decreased to cause DA deficiency in the striatum in PD. However, the homo-specific activity (activity/enzyme protein) of TH is increased. This increase in TH homo-specific activity suggests activation by increased phosphorylation at the N-terminus of the TH protein for a compensatory increase in DA synthesis. We recently found that phosphorylation of the N-terminal portion of TH triggers proteasomal degradation of the enzyme to increase TH turnover. We propose a hypothesis that this compensatory activation of TH by phosphorylation in the remaining DA neurons may contribute to a further decrease in TH protein and activity in DA neurons in PD, causing a vicious circle of decreasing TH activity, protein level and DA contents. Furthermore, increased TH homo-specific activity leading to an increase in DA may cause toxic reactive oxygen species in the neurons to promote neurodegeneration.

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References

  • Baptista MJ, O’Farrell C, Days S, Ahmad R, Miller DW, Hardy J, Farrer MJ, Cookson MR (2003) Coordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines. J Neurochem 85:957–968

    Article  PubMed  CAS  Google Scholar 

  • Bisaglia M, Soriano ME, Arduini I, Mammi S, Bubacco L (2010) Molecular characterization of dopamine-derived quinones reacting toward NADH and glutathione: implications for mitochondrial dysfunction in Parkinson disease. Biochim Biophys Acta 1802:699–706

    Article  PubMed  CAS  Google Scholar 

  • Bonifati V (2012) Autosomal recessive parkinsonism. Parkinsonism Relat Disord 18S1, S4–S6

  • Carlsson A (1959) The occurrence, distribution and physiological role of dopamine in the nervous system. Pharmacol Rev 11:490–493

    PubMed  CAS  Google Scholar 

  • Døskeland AP, Flatmark T (2002) Ubiquitination of soluble and membrane bound tyrosine hydroxylase and degradation of the soluble form. Eur J Biochem 269:1561–1569

    Article  PubMed  Google Scholar 

  • Ehringer H, Hornykiewicz O (1960) Verteilung von Noradrenalin und Dopamin (3-HYdroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des Extrapyramidaren Systems. Klin Wochenschr 38:1236–1239

    Article  PubMed  CAS  Google Scholar 

  • Foley P, Mizuno Y, Nagatsu T, Sano A, Youdim MBH, McGeer P, McGeer P, Riederer P (2000) The L-dopa story—an early Japanese contribution. Parkinsonism Relat Disord 6:1–6

    Article  Google Scholar 

  • Gao N, Li YH, Li X, Yu S, Fu GL, Chen B (2007) Effect of α-synuclein on the promoter activity of tyrosine hydroxylase gene. Neurosci Bull 23:53–57

    Article  PubMed  CAS  Google Scholar 

  • Gasser T, Hardy J, Mizuno Y (2011) Milestones in PD genetics. Mov Disord 26:1042–1048

    Article  PubMed  Google Scholar 

  • Goldstein DS, Holmes C, Cannon RO, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. New Engl J Med 336:692–702

    Article  Google Scholar 

  • Grima B, Lamouroux A, Boni C, Julian J-F, Javoy-Agid F, Mallet J (1987) A single human gene encoding multiple tyrosine hydroxylase with different predicted functional characteristics. Nature 326:707–711

    Article  PubMed  CAS  Google Scholar 

  • Hattori N (2012) Autosomal dominant parkinsonism: its etiologies and differential diagnoses. Parkinsonism Relat Disord 18S1:S1–S3

    Google Scholar 

  • Ichinose H, Ohye T, Fujita K, Yoshida M, Ueda S, Nagatsu T (1993) Increased heterogeneity of tyrosine hydroxylase in humans. Biochem Biophys Res Commun 195:158–165

    Article  PubMed  CAS  Google Scholar 

  • Ichinose H, Ohye T, Fujita K, Pantucek F, Lange K, Riederer P, Nagatsu T (1994) Quantitation of mRNA of tyrosine hydroxylase and aromatic amino acid decarboxylase in the substantia nigra in Parkinson’s disease and schizophrenia. J Neural Transm 8:149–158 (P–D Sect)

    Article  CAS  Google Scholar 

  • Itagaki C, Isobe T, Taoka M, Natsume T, Nomura N, Horigome T, Omura S, Ichinose H, Nagatsu T, Greene LA, Ishimura T (1999) Stimulus-coupled interaction of tyrosine hydroxylase with 14-3-3 proteins. Biochemistry 38:15673–15680

    Article  PubMed  CAS  Google Scholar 

  • Kaneda N, Kobayashi K, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T (1987) Isolation of a novel cDNA clone for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene. Biochem Biophys Res Commun 146:971–975

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi K, Nagatsu T (2005) Molecular genetics of tyrosine 3-monooxygenase and inherited diseases. Biochem Biophys Res Commun 338:267–270

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi K, Kaneda N, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T (1988) Structure of the human tyrosine hydroxylase gene: alternative splicing from a single gene accounts for generation of four mRNA types. J Biochem 103:907–912

    PubMed  CAS  Google Scholar 

  • Kvetnansky R, Sabban EL, Palkovits M (2009) Catecholamine systems in stress: structural and molecular approaches. Physiol Rev 89:535–606

    Article  PubMed  CAS  Google Scholar 

  • Lehman IT, Bobrovskaya L, Gordon SL, Dunkley PR, Dickson PW (2006) Differential regulation of the human tyrosine hydroxylase isoforms via hierarchical phosphorylation. J Biol Chem 281:17644–17651

    Article  Google Scholar 

  • Lesage S, Brice A (2012) Role of Mendelian genes in “sporadic” Parkinson’s disease. Parkinsonism Relat Disord 18S1:S66–S70

    Article  Google Scholar 

  • Lopez Verrilli MA, Pirola CJ, Pascual MM, Dominici FP, Turyn D, Gironacci MM (2009) Angiotensin-(1–7) through AT receptors mediates tyrosine hydroxylase degradation via the ubiquitin-proteasome pathway. J Neurochem 109:326–335

    Article  PubMed  Google Scholar 

  • Mazzuli JR, Mishizen AJ, Giasson BI, Lynch DR, Thomas SA, Nakashima A, Nagatsu T, Ota A, Ischiropoulos H (2006) Cytosolic catecholamines inhibit α-synuclein aggregation and facilitate the formation of intracellular soluble oligomeric intermediates. J Neurosci 26:10068–10078

    Article  Google Scholar 

  • McGeer EG, McGeer PL (2007) The role of inflammatory agents in Parkinson’s disease. CNS Drugs 21:789–797

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s disease and Alzheimer’s disease brain. Neurology 38:1285–1291

    Article  PubMed  CAS  Google Scholar 

  • McNaught KS, Jackson T, JnoBaptiste R, Kapustin A, Olanow CW (2006) Proteasomal dysfunction in sporadic Parkinson disease. Neurology 66:S37–S49

    Article  PubMed  CAS  Google Scholar 

  • Mizuno Y, Hattori N, Yoshino H, Hatano Y, Satoh K, Tomiyama H, Li Y (2006) Progress in familial Parkinson’s disease. J Neural Transm Suppl 70:191–204

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, Harada M, Kiuchi K, Kojima K, Kondo T, Narabayashi H, Rausch D, Riederer P, Nagatsu T (1988a) Homospecific activity (activity per enzyme protein) of tyrosine hydroxylase increases in Parkinsonian brain. J Neural Transm 72:77–81

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, Harada M, Kojima K, Inagaki H, Kondo T, Narabayashi H, Arai R, Fujita K, Kiuchi K, Nagatsu T (1988b) Sandwich enzyme immunoassay of dopamine-β-hydroxylase in cerebrospinal fluid from control and parkinsonian patients. Neurochem Int 12:187–191

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T (1977) Dopamine-β-hydroxylase in blood and cerebrospinal fluid. Trends Biochem Sci 2:217–219

    Article  CAS  Google Scholar 

  • Nagatsu T (1991) Genes for human catecholamine synthesizing enzymes. Neurosci Res 12:315–345

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T (1995) Tyrosine hydroxylase: human isoforms, structure and regulation in physiology and pathology. Essays Biochem 30:15–35

    PubMed  CAS  Google Scholar 

  • Nagatsu T (2006) The catecholamine system in health and disease: relation to tyrosine 3-monooxygenase and other catecholamine-synthesizing enzymes. Proc Jpn Acad B Phys Biol Sci 82:388–415

    Article  CAS  Google Scholar 

  • Nagatsu T, Sawada M (2005) Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 11:999–1016

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T, Sawada M (2006) Cellular and molecular mechanisms of Parkinson’s disease: neurotoxins, causative genes, and inflammatory cytokines. Cell Mol Neurobiol 26:779–800

    Article  Google Scholar 

  • Nagatsu T, Sawada M (2007) Biochemistry of postmortem brains in Parkinson’s disease: historical overview and future prospects. J Neural Transm Suppl 72:113–120

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T, Stjärne L (1995) Catecholamine synthesis and release. Overv Adv Pharmacol 42:1–14

    Article  Google Scholar 

  • Nagatsu T, Kato T, Numata (Sudo) Y, Ikuta K, Sano M, Nagatsu I, Kondo Y, Inagaki S, Iizuka R, Hori A, Narabayashi H (1977) Phenylethanolamine N-methyltransferase and other enzymes of catecholamine metabolism in human brain. Clin Chim Acta 75:221–232

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T, Mogi M, Ichinose H, Togari A, Riederer P (1999) Cytokines in Parkinson’s disease. Neurosci News 2:88–90

    CAS  Google Scholar 

  • Nakashima A (2010) Proteasomal degradation of tyrosine hydroxylase and neurodegeneration. J Neurochem 120:199–201

    Article  Google Scholar 

  • Nakashima A, Mori K, Kaneko YS, Hayashi N, Nagatsu T, Ota A (2011) Phosphorylation of the N-terminal portion of tyrosine hydroxylase triggers proteasomal digestion of the enzyme. Biochem Biophys Res Commun 407:343–347

    Article  PubMed  CAS  Google Scholar 

  • O’Malley KL, Anhalt MJ, Martin BM, Kelsoe JR, Winfield SL, Ginns EI (1987) Isolation and characterisation of the human tyrosine hydroxylase gene: identification of 5′ alternative sites responsible for multiple mRNAs. Biochimistry 26:6910–6914

    Article  Google Scholar 

  • Ohye T, Ichinose H, Ogawa M, Yoshida M, Nagatsu T (1995) Alterations in multiple tyrosine hydroxylase mRNAs in the substantia nigra, locus coeruleus and adrenal gland of MPTP-treated parkinsonian monkeys. Neurodegeneration 4:81–85

    Article  PubMed  CAS  Google Scholar 

  • Peng X, Tehranian R, Dietrich P, Stefanis L, Perez RG (2005) α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopamine cells. J Cell Sci 118:3523–3530

    Article  PubMed  CAS  Google Scholar 

  • Perez RG, Waymire JC, Lin E, Liu JJ, Gao F, Zigmond MJ (2002) A role for α-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22:3090–3099

    PubMed  CAS  Google Scholar 

  • Rausch WD, Hirata Y, Nagatsu T, Riederer P, Jellinger K (1988) Tyrosine hydroxylase activity in caudate nucleus from Parkinson’s disease: effects of iron and phosphorylating agents. J Neurochem 50:202–208

    Article  PubMed  CAS  Google Scholar 

  • Riederer P, Reichmann H, Janetzky K-P, Sian J, Lesch K-P, Lange KW, Double KL, Nagatsu T, Gerlach M (2001) Neural degeneration in Parkinson’s disease. In: Calne D, Calne S (eds) Parkinson’s disease: Adv Neurol 86. Lippincott Wiliams & Wilkins, Philadelphia, pp 125–136

    Google Scholar 

  • Sandal C, Fujioka S, Uitti RJ, Wszolek K (2012) Autosomal dominant Parkinson’s disease. Parkinsonism Relat Disord 18S1, S57–S10

  • Shi X, Habecker BA (2011) gp130 cytokines stimulate proteasomal degradation of tyrosine hydroxylase via extracellular signal regulated kinase 1 and 2. J Neurochem 120:239–247

    Article  PubMed  Google Scholar 

  • Suzanne L, Brice A (2012) Role of Mendelian genes in “sporadic” Parkinson’s disease. Parkinsonism Relat Disord 18S1:S66–S70

    Google Scholar 

  • Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518

    Article  PubMed  CAS  Google Scholar 

  • Ugrumov MV, Khaindrava VG, Kozina EA, Kucheryanu VG, Bocharov EV, Kryzhanovsky GN, Kudrin VS, Narkevich VB, Klodt PM, Rayevsky KS, Pronina TS (2011) Modeling of presynaptic and symptomatic stages of Parkinsonism in mice. Neuroscience 181:175–188

    Article  PubMed  CAS  Google Scholar 

  • Venda LL, Cragg SJ, Buchman VL, Wade-Martins R (2011) α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends Neurosci 33:559–568

    Article  Google Scholar 

  • Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA (2002) Dopamine-dependent neurotoxicity of α-synuclein: a mechanism for selective neurodegeneration in Parkinson’s disease. Nat Med 8:600–606

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Prof. Peter Riederer for his collaboration with us on the biochemistry of the post mortem brain by providing samples from his brain bank at the University of Würzburg. We dedicate this review manuscript to Prof. Peter Riederer, who is celebrating his 70th birthday.

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Authors and Affiliations

  1. Department of Physiology, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan

    Akira Nakashima, Akira Ota, Yoko S. Kaneko, Keiji Mori & Hiroshi Nagasaki

  2. Department of Pharmacology, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan

    Toshiharu Nagatsu

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  1. Akira Nakashima
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  2. Akira Ota
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  3. Yoko S. Kaneko
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  6. Toshiharu Nagatsu
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Correspondence to Toshiharu Nagatsu.

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Nakashima, A., Ota, A., Kaneko, Y.S. et al. A possible pathophysiological role of tyrosine hydroxylase in Parkinson’s disease suggested by postmortem brain biochemistry: a contribution for the special 70th birthday symposium in honor of Prof. Peter Riederer. J Neural Transm 120, 49–54 (2013). https://doi.org/10.1007/s00702-012-0828-5

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