Home LiteratureArticle Details
PMID: 11943812 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A role for alpha-synuclein in the regulation of dopamine biosynthesis.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 8 ·2002-04-15 ·Pages 3090-9

Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ

Abstract

The alpha-synuclein gene is implicated in the pathogenesis of Parkinson's disease. Although alpha-synuclein function is uncertain, the protein has homology to the chaperone molecule 14-3-3. In addition, alpha-synuclein can bind to 14-3-3, and both alpha-synuclein and 14-3-3 bind to many of the same proteins. Because 14-3-3 binds to and activates tyrosine hydroxylase, the rate-limiting enzyme in dopamine (DA) biosynthesis, we explored whether alpha-synuclein also bound to tyrosine hydroxylase and influenced its activity. Immunoprecipitation revealed an interaction between alpha-synuclein and tyrosine hydroxylase in brain homogenates and MN9D dopaminergic cells. Colocalization of alpha-synuclein with tyrosine hydroxylase was confirmed by immunoelectron microscopy. To explore the consequences of the interaction, we measured the effect of recombinant alpha-synuclein on tyrosine hydroxylase activity in a cell-free system and observed a dose-dependent inhibition of tyrosine hydroxylase by alpha-synuclein. To measure the impact of alpha-synuclein on tyrosine hydroxylase in dopaminergic cells, we stably transfected MN9D cells with wild-type or A53T mutant alpha-synuclein. Overexpression of wild-type or A53T mutant alpha-synuclein did not significantly alter tyrosine hydroxylase protein levels in our stably transfected cells. However, overexpressing cell lines had significantly reduced tyrosine hydroxylase activity and a corresponding reduction in dopamine synthesis. The reduction in cellular dopamine levels was not caused by increased dopamine catabolism or dopamine efflux. These data suggest that alpha-synuclein plays a role in the regulation of dopamine biosynthesis, acting to reduce the activity of tyrosine hydroxylase. If so, a loss of soluble alpha-synuclein, by reduced expression or aggregation, could increase dopamine synthesis with an accompanying increase in reactive dopamine metabolites.

MeSH Terms
Amino Acid Substitution Animals Brain/metabolism Brain Chemistry Cell Line Cell Survival Cell-Free System/metabolism Dopamine/metabolism Enzyme Activation/physiology Gene Expression Hybrid Cells/metabolism,ultrastructure Mice Mice, Inbred C57BL Microscopy, Immunoelectron Models, Biological Nerve Tissue Proteins/chemistry,genetics,metabolism Neurons/metabolism,ultrastructure Parkinson Disease/etiology,metabolism Phosphorylation Precipitin Tests Protein Binding/physiology Synucleins Transfection Tyrosine 3-Monooxygenase/chemistry,metabolism alpha-Synuclein
Chemicals
Nerve Tissue Proteins Snca protein, mouse Synucleins alpha-Synuclein Tyrosine 3-Monooxygenase Dopamine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Perez Ruth G
Department of Neurology and Center for Biological Imaging, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. [email protected]
Waymire Jack C
Lin Eva
Liu Jen J
Guo Fengli
Zigmond Michael J
References (71)
71 references, click to expand
  1. Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins.
    Biochemistry. 1998 Apr 7;37(14):4901-9 PMID: 9538008
  2. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.
    Science. 1997 Jun 27;276(5321):2045-7 PMID: 9197268
  3. TYROSINE HYDROXYLASE. THE INITIAL STEP IN NOREPINEPHRINE BIOSYNTHESIS.
    J Biol Chem. 1964 Sep;239:2910-7 PMID: 14216443
  4. Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis.
    FASEB J. 2001 Apr;15(6):916-26 PMID: 11292651
  5. Enhanced release of amyloid beta-protein from codon 670/671 "Swedish" mutant beta-amyloid precursor protein occurs in both secretory and endocytic pathways.
    J Biol Chem. 1996 Apr 12;271(15):9100-7 PMID: 8621560
  6. Age-related dopamine deficiency in the mesostriatal dopamine system of zitter mutant rats: regional fiber vulnerability in the striatum and the olfactory tubercle.
    Neuroscience. 2000;95(2):389-98 PMID: 10658618
  7. MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons.
    Neuroreport. 2000 Jan 17;11(1):211-3 PMID: 10683860
  8. Interaction of phosphorylated tyrosine hydroxylase with 14-3-3 proteins: evidence for a phosphoserine 40-dependent association.
    J Neurochem. 2001 May;77(4):1097-107 PMID: 11359875
  9. Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation.
    J Biol Chem. 1998 Oct 9;273(41):26292-4 PMID: 9756856
  10. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.
    Nat Genet. 1998 Feb;18(2):106-8 PMID: 9462735
  11. Raf-1 kinase and exoenzyme S interact with 14-3-3zeta through a common site involving lysine 49.
    J Biol Chem. 1997 May 23;272(21):13717-24 PMID: 9153224
  12. Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections.
    Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1956-61 PMID: 8700866
  13. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
    Cell. 1999 Mar 19;96(6):857-68 PMID: 10102273
  14. Inhibition of dopamine synthesis by dopamine D2 and D3 but not D4 receptors.
    J Pharmacol Exp Ther. 1996 Apr;277(1):186-92 PMID: 8613917
  15. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies.
    Proc Natl Acad Sci U S A. 1998 May 26;95(11):6469-73 PMID: 9600990
  16. Neuropathology in mice expressing human alpha-synuclein.
    J Neurosci. 2000 Aug 15;20(16):6021-9 PMID: 10934251
  17. Alpha-synuclein in Lewy bodies.
    Nature. 1997 Aug 28;388(6645):839-40 PMID: 9278044
  18. Stimulus-coupled interaction of tyrosine hydroxylase with 14-3-3 proteins.
    Biochemistry. 1999 Nov 23;38(47):15673-80 PMID: 10569954
  19. Use of poly(vinylpyrrolidone) and poly(vinyl alcohol) for cryoultramicrotomy.
    Histochem J. 1989 Mar;21(3):163-71 PMID: 2722561
  20. Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro.
    J Biol Chem. 1999 Mar 19;274(12):7619-22 PMID: 10075647
  21. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders.
    Science. 2000 Feb 18;287(5456):1265-9 PMID: 10678833
  22. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.
    Neuron. 2000 Jan;25(1):239-52 PMID: 10707987
  23. Human recombinant NACP/alpha-synuclein is aggregated and fibrillated in vitro: relevance for Lewy body disease.
    Brain Res. 1998 Jul 20;799(2):301-6 PMID: 9675319
  24. Alpha-synuclein expression in substantia nigra and cortex in Parkinson's disease.
    Mov Disord. 1999 May;14(3):417-22 PMID: 10348463
  25. 14-3-3 proteins: regulation of subcellular localization by molecular interference.
    Cell Signal. 2000 Dec;12(11-12):703-9 PMID: 11152955
  26. Chaperone-like activity of synucleins.
    FEBS Lett. 2000 May 26;474(1):116-9 PMID: 10828462
  27. Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons.
    Brain Res Dev Brain Res. 1997 Mar 17;99(1):87-94 PMID: 9088569
  28. Synucleinopathies: clinical and pathological implications.
    Arch Neurol. 2001 Feb;58(2):186-90 PMID: 11176955
  29. Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death.
    J Neurosci. 2001 Dec 15;21(24):9549-60 PMID: 11739566
  30. Intricate regulation of tyrosine hydroxylase activity and gene expression.
    J Neurochem. 1996 Aug;67(2):443-62 PMID: 8764568
  31. Subcellular localization of alpha-2A-adrenergic receptors in the rat medial nucleus tractus solitarius: regional targeting and relationship with catecholamine neurons.
    J Comp Neurol. 2001 Apr 30;433(2):193-207 PMID: 11283959
  32. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons.
    J Neurosci. 2000 May 1;20(9):3214-20 PMID: 10777786
  33. Abnormal distribution of the non-Abeta component of Alzheimer's disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment.
    Lab Invest. 1998 Sep;78(9):1169-77 PMID: 9759660
  34. Leonardo, a Drosophila 14-3-3 protein involved in learning, regulates presynaptic function.
    Neuron. 1997 Aug;19(2):391-402 PMID: 9292728
  35. Impact of L-dopa on striatal acetylcholine release: effects of 6-hydroxydopamine.
    J Pharmacol Exp Ther. 1993 Nov;267(2):912-8 PMID: 8246167
  36. alpha-Synuclein shares physical and functional homology with 14-3-3 proteins.
    J Neurosci. 1999 Jul 15;19(14):5782-91 PMID: 10407019
  37. The parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity.
    J Biol Chem. 2000 Dec 8;275(49):38581-8 PMID: 10969076
  38. Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation.
    J Biol Chem. 1999 Apr 2;274(14):9843-6 PMID: 10092675
  39. Ultrastructural localization of the vesicular monoamine transporter-2 in midbrain dopaminergic neurons: potential sites for somatodendritic storage and release of dopamine.
    J Neurosci. 1996 Jul 1;16(13):4135-45 PMID: 8753875
  40. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct.
    Science. 2001 Nov 9;294(5545):1346-9 PMID: 11701929
  41. Review: formation and properties of amyloid-like fibrils derived from alpha-synuclein and related proteins.
    J Struct Biol. 2000 Jun;130(2-3):300-9 PMID: 10940234
  42. Cytotoxic and genotoxic potential of dopamine.
    J Neurosci Res. 1999 Mar 15;55(6):659-65 PMID: 10220107
  43. Molecular cloning of cDNA coding for brain-specific 14-3-3 protein, a protein kinase-dependent activator of tyrosine and tryptophan hydroxylases.
    Proc Natl Acad Sci U S A. 1988 Oct;85(19):7084-8 PMID: 2902623
  44. Activation of protein kinase C by purified bovine brain 14-3-3: comparison with tyrosine hydroxylase activation.
    J Neurochem. 1994 Nov;63(5):1908-16 PMID: 7931346
  45. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones.
    Mol Pharmacol. 1978 Jul;14(4):633-43 PMID: 98706
  46. Structural changes in alpha-synuclein affect its chaperone-like activity in vitro.
    Protein Sci. 2000 Dec;9(12):2489-96 PMID: 11206070
  47. Determination of dopa, dopamine, dopac, epinephrine, norepinephrine, alpha-monofluoromethyldopa and alpha-difluoromethyldopa in various tissues of mice and rats using reversed-phase ion-pair liquid chromatography with electrochemical detection.
    J Chromatogr. 1979 Sep 11;164(1):41-54 PMID: 541397
  48. Ultrastructural localization of tyrosine hydroxylase in noradrenergic neurons of brain.
    Proc Natl Acad Sci U S A. 1975 Feb;72(2):659-63 PMID: 235760
  49. Vasoactive intestinal peptide stimulates catecholamine biosynthesis in isolated adrenal chromaffin cells: evidence for a cyclic AMP-dependent phosphorylation and activation of tyrosine hydroxylase.
    J Neurochem. 1991 Oct;57(4):1313-24 PMID: 1680163
  50. Clinical genetic analysis of Parkinson's disease in the Contursi kindred.
    Ann Neurol. 1996 Nov;40(5):767-75 PMID: 8957018
  51. Phosphorylation of Ser(19) alters the conformation of tyrosine hydroxylase to increase the rate of phosphorylation of Ser(40).
    J Biol Chem. 2001 Nov 2;276(44):40411-6 PMID: 11502746
  52. Specific modulation of dopamine expression in neuronal hybrid cells by primary cells from different brain regions.
    Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8943-7 PMID: 1357658
  53. A rapid and sensitive assay for tyrosine-3-monooxygenase based upon the release of 3H2O and adsorption of [3H]-tyrosine by charcoal.
    Life Sci. 1986 Dec 8;39(23):2185-9 PMID: 2878337
  54. Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous system.
    J Neuropathol Exp Neurol. 1996 Aug;55(8):889-95 PMID: 8759778
  55. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.
    Nat Med. 1998 Nov;4(11):1318-20 PMID: 9809558
  56. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal.
    J Neurosci. 1988 Aug;8(8):2804-15 PMID: 3411354
  57. Phosphorylation of bovine adrenal chromaffin cell tyrosine hydroxylase. Temporal correlation of acetylcholine's effect on site phosphorylation, enzyme activation, and catecholamine synthesis.
    J Biol Chem. 1988 Sep 5;263(25):12439-47 PMID: 2900836
  58. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes.
    J Biol Chem. 1998 Apr 17;273(16):9443-9 PMID: 9545270
  59. Understanding cell death in Parkinson's disease.
    Ann Neurol. 1998 Sep;44(3 Suppl 1):S72-84 PMID: 9749577
  60. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter.
    Cell. 1992 Aug 21;70(4):539-51 PMID: 1505023
  61. Protein kinase C activation by acidic proteins including 14-3-3.
    Biochem J. 2000 May 1;347 Pt 3:781-5 PMID: 10769183
  62. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations.
    J Neurol Sci. 1973 Dec;20(4):415-55 PMID: 4272516
  63. Accelerated oligomerization by Parkinson's disease linked alpha-synuclein mutants.
    Ann N Y Acad Sci. 2000;920:42-5 PMID: 11193175
  64. Overexpression of human alpha-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells.
    Brain Res. 2000 Jun 2;866(1-2):33-43 PMID: 10825478
  65. Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter.
    Neurobiol Dis. 2001 Jun;8(3):535-9 PMID: 11442360
  66. Reduced expression of the G209A alpha-synuclein allele in familial Parkinsonism.
    Ann Neurol. 1999 Sep;46(3):374-81 PMID: 10482268
  67. Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40.
    J Biol Chem. 1990 Jul 15;265(20):11682-91 PMID: 1973163
  68. Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42.
    J Biol Chem. 1999 Jul 2;274(27):18851-6 PMID: 10383380
  69. Immortalization of embryonic mesencephalic dopaminergic neurons by somatic cell fusion.
    Brain Res. 1991 Jun 21;552(1):67-76 PMID: 1913182
  70. Chronic systemic pesticide exposure reproduces features of Parkinson's disease.
    Nat Neurosci. 2000 Dec;3(12):1301-6 PMID: 11100151
  71. A Drosophila model of Parkinson's disease.
    Nature. 2000 Mar 23;404(6776):394-8 PMID: 10746727
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
20026307
Email
[email protected]
Published
2002-04-15
Pages
3090-9
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757524
Subset
IM
Grants
NINDS NIH HHS · P01 NS019608 · United States
NINDS NIH HHS · R01 NS042094 · United States
NINDS NIH HHS · NS19608 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 20026307 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2