Neurochemical Research

, Volume 41, Issue 8, pp 2102–2109 | Cite as

Exogenous α-Synuclein Monomers Alter Dopamine Metabolism in Murine Brain

  • Adriana Wawer
  • Ilona Joniec-Maciejak
  • Anna Sznejder-Pachołek
  • Joanna Schwenkgrub
  • Agnieszka Ciesielska
  • Dagmara Mirowska-Guzel
Original Paper


Alpha-synuclein (ASN) is a small presynaptic protein which is the major component of Lewy bodies—the histological hallmark of Parkinson’s disease. Among many functions, ASN plays an important role in regulation of dopaminergic system by controlling dopamine concentration at nerve terminals. An abnormal structure or excessive accumulation of ASN in the brain can induce neurotoxicity leading to the dopaminergic neurodegeneration. To date, several transgenic mouse lines overexpressing ASN have been generated and there are several studies using injections of ASN fibrils into the murine brain. However, still is little known about the effects of exogenously applied ASN monomers on dopaminergic neurotransmission. In this study we investigated the influence of cerebral injection of human ASN on dopaminergic system activity. We have demonstrated that a single injection of ASN monomers into the substantia nigra pars compacta or striatum is sufficient to affect dopaminergic neurotransmission in murine nigro-striatal system.


Alpha-synuclein Dopamine Dopaminergic system Parkinson’s disease Tyrosine hydroxylase 



This study was supported by Grant No. N N401 066638 from the Ministry of Science and Higher Education, Warsaw, Poland. Project implemented with CePT infrastructure financed by the European Union—The European Regional Development Fund within the operational program ‘‘Innovative economy’’ for 2007–2013.


  1. 1.
    Lee VM, Trojanowski JQ (2006) Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 52(1):33–38CrossRefPubMedGoogle Scholar
  2. 2.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science (New York, NY) 276(5321):2045–2047CrossRefGoogle Scholar
  3. 3.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55(2):164–173CrossRefPubMedGoogle Scholar
  4. 4.
    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18(2):106–108CrossRefPubMedGoogle Scholar
  5. 5.
    Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, Weir D, Thompson C, Szu-Tu C, Trinh J, Aasly JO, Rajput A, Rajput AH, Jon Stoessl A, Farrer MJ (2013) Alpha-synuclein p. H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov Disord 28(6):811–813CrossRefPubMedGoogle Scholar
  6. 6.
    Lesage S, Anheim M, Letournel F, Bousset L, Honore A, Rozas N, Pieri L, Madiona K, Durr A, Melki R, Verny C, Brice A (2013) G51D alpha-synuclein mutation causes a novel parkinsonian–pyramidal syndrome. Ann Neurol 73(4):459–471CrossRefPubMedGoogle Scholar
  7. 7.
    Ghosh D, Sahay S, Ranjan P, Salot S, Mohite GM, Singh PK, Dwivedi S, Carvalho E, Banerjee R, Kumar A, Maji SK (2014) The newly discovered Parkinson’s disease associated Finnish mutation (A53E) attenuates alpha-synuclein aggregation and membrane binding. Biochemistry 53(41):6419–6421CrossRefPubMedGoogle Scholar
  8. 8.
    Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destee A (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364(9440):1167–1169CrossRefPubMedGoogle Scholar
  9. 9.
    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science (New York, NY) 302(5646):841CrossRefGoogle Scholar
  10. 10.
    Venda LL, Cragg SJ, Buchman VL, Wade-Martins R (2010) alpha-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends Neurosci 33(12):559–568CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lotharius J, Brundin P (2002) Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson’s disease. Hum Mol Genet 11(20):2395–2407CrossRefPubMedGoogle Scholar
  12. 12.
    Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22(8):3090–3099PubMedGoogle Scholar
  13. 13.
    Wersinger C, Sidhu A (2003) Attenuation of dopamine transporter activity by alpha-synuclein. Neurosci Lett 340(3):189–192CrossRefPubMedGoogle Scholar
  14. 14.
    Pelkonen A, Kallunki P, Yavich L (2013) Effects of exogenous alpha-synuclein on stimulated dopamine overflow in dorsal striatum. Neurosci Lett 554:141–145CrossRefPubMedGoogle Scholar
  15. 15.
    Wersinger C, Prou D, Vernier P, Sidhu A (2003) Modulation of dopamine transporter function by alpha-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress. FASEB J 17(14):2151–2153PubMedGoogle Scholar
  16. 16.
    Bartels T, Choi JG, Selkoe DJ (2011) alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362):107–110CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Joniec-Maciejak I, Ciesielska A, Wawer A, Sznejder-Pacholek A, Schwenkgrub J, Cudna A, Hadaczek P, Bankiewicz KS, Czlonkowska A, Czlonkowski A (2014) The influence of AAV2-mediated gene transfer of human IL-10 on neurodegeneration and immune response in a murine model of Parkinson’s disease. Pharmacol Rep 66(4):660–669CrossRefPubMedGoogle Scholar
  18. 18.
    West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231(4):482–497CrossRefPubMedGoogle Scholar
  19. 19.
    Yu S, Zuo X, Li Y, Zhang C, Zhou M, Zhang YA, Ueda K, Chan P (2004) Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells. Neurosci Lett 367(1):34–39CrossRefPubMedGoogle Scholar
  20. 20.
    Tehranian R, Montoya SE, Van Laar AD, Hastings TG, Perez RG (2006) Alpha-synuclein inhibits aromatic amino acid decarboxylase activity in dopaminergic cells. J Neurochem 99(4):1188–1196CrossRefPubMedGoogle Scholar
  21. 21.
    Alerte TN, Akinfolarin AA, Friedrich EE, Mader SA, Hong CS, Perez RG (2008) Alpha-synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: lessons from viral transduction of knockout mice. Neurosci Lett 435(1):24–29CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lam HA, Wu N, Cely I, Kelly RL, Hean S, Richter F, Magen I, Cepeda C, Ackerson LC, Walwyn W, Masliah E, Chesselet MF, Levine MS, Maidment NT (2011) Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human alpha-synuclein. J Neurosci Res 89(7):1091–1102CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science (New York, NY) 287(5456):1265–1269CrossRefGoogle Scholar
  24. 24.
    Wakamatsu M, Ishii A, Iwata S, Sakagami J, Ukai Y, Ono M, Kanbe D, Muramatsu S, Kobayashi K, Iwatsubo T, Yoshimoto M (2008) Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice. Neurobiol Aging 29(4):574–585CrossRefPubMedGoogle Scholar
  25. 25.
    Decressac M, Mattsson B, Lundblad M, Weikop P, Bjorklund A (2012) Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of alpha-synuclein in midbrain dopamine neurons. Neurobiol Dis 45(3):939–953CrossRefPubMedGoogle Scholar
  26. 26.
    Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Bjorklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22(7):2780–2791PubMedGoogle Scholar
  27. 27.
    Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53→ Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99(13):8968–8973CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S, Sondel J, Kotilinek L, Day J, Schwarzschild MA, Cha JH, Newell K, Miller DW, Ueda K, Young AB, Hyman BT, Ashe KH (2003) Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice. Neurobiol Aging 24(2):245–258CrossRefPubMedGoogle Scholar
  29. 29.
    Tofaris GK, Garcia Reitbock P, Humby T, Lambourne SL, O’Connell M, Ghetti B, Gossage H, Emson PC, Wilkinson LS, Goedert M, Spillantini MG (2006) Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein (1–120): implications for Lewy body disorders. J Neurosci 26(15):3942–3950CrossRefPubMedGoogle Scholar
  30. 30.
    Cabeza-Arvelaiz Y, Fleming SM, Richter F, Masliah E, Chesselet MF, Schiestl RH (2011) Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons. Mol Neurodegener 6:83CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zigmond MJ, Acheson AL, Stachowiak MK, Stricker EM (1984) Neurochemical compensation after nigrostriatal bundle injury in an animal model of preclinical parkinsonism. Arch Neurol 41(8):856–861CrossRefPubMedGoogle Scholar
  32. 32.
    Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 13(7):290–296CrossRefPubMedGoogle Scholar
  33. 33.
    Graham DG (1978) Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 14(4):633–643PubMedGoogle Scholar
  34. 34.
    Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science (New York, NY) 294(5545):1346–1349CrossRefGoogle Scholar
  35. 35.
    Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA (2002) Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med 8(6):600–606CrossRefPubMedGoogle Scholar
  36. 36.
    Lotharius J, Barg S, Wiekop P, Lundberg C, Raymon HK, Brundin P (2002) Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 277(41):38884–38894CrossRefPubMedGoogle Scholar
  37. 37.
    Chen NH, Reith ME, Quick MW (2004) Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch 447(5):519–531CrossRefPubMedGoogle Scholar
  38. 38.
    Sidhu A, Wersinger C, Vernier P (2004) α-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson’s disease. FEBS Lett 565(1):1–5CrossRefPubMedGoogle Scholar
  39. 39.
    Lee FJ, Liu F, Pristupa ZB, Niznik HB (2001) Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. FASEB J 15(6):916–926CrossRefPubMedGoogle Scholar
  40. 40.
    Adamczyk A, Kazmierczak A, Strosznajder JB (2006) Alpha-synuclein and its neurotoxic fragment inhibit dopamine uptake into rat striatal synaptosomes: relationship to nitric oxide. Neurochem Int 49(4):407–412CrossRefPubMedGoogle Scholar
  41. 41.
    Oaks AW, Sidhu A (2011) Synuclein modulation of monoamine transporters. FEBS Lett 585(7):1001–1006CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science (New York, NY) 338(6109):949–953CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Adriana Wawer
    • 1
  • Ilona Joniec-Maciejak
    • 1
  • Anna Sznejder-Pachołek
    • 1
  • Joanna Schwenkgrub
    • 1
  • Agnieszka Ciesielska
    • 2
  • Dagmara Mirowska-Guzel
    • 1
    • 3
  1. 1.Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePTMedical University of WarsawWarsawPoland
  2. 2.Department of NeurosurgeryUniversity of California at San FranciscoSan FranciscoUSA
  3. 3.2nd Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland

Personalised recommendations