Jump to ContentJump to Main Navigation
Show Summary Details
More options …


Organ der Neurowissenschaftlichen Gesellschaft

Editor-in-Chief: Wahle, Petra

CiteScore 2018: 0.11

SCImago Journal Rank (SJR) 2018: 0.134
Source Normalized Impact per Paper (SNIP) 2018: 0.047

See all formats and pricing
More options …
Volume 25, Issue 2


Alpha-synuclein as therapeutic target in Parkinson’s disease

Prof. Dr. Franziska Richter Assêncio
  • Corresponding author
  • Chair, Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Buenteweg 17, D-30559 Hannover phone: +49-511-953-8720 Fax: +49-511-953-8581 Hannover Germany
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2019-06-04 | DOI: https://doi.org/10.1515/nf-2018-0029


180 Jahre vergingen zwischen James Parkinson’s “An essay on the shaking palsy” und der Entdeckung der zentralen Rolle von alpha-synuclein in der Pathogenese von Parkinson’s disease (PD). Der Identifikation einer PD verursachenden Mutation im alpha-synuclein Gen folgte rasch der Nachweis des Proteins in Lewy Körperchen, den charakteristischen Proteineinschlüssen im Gehirn der Patienten. Trotz vieler ungeklärter Fragen, Forschungsergebnisse zur Entstehung, Ausbreitung und Neurotoxizität der alpha-synuclein Pathologie geben Hoffnung auf die Entwicklung einer Krankheits-modifizierenden Therapie, über die Dopaminersatztherapie hinaus. Die Hypothese, dass alpha-synuclein Pathologie sich ähnlich wie ein Prion ausbreitet, wird kontrovers diskutiert, und initiierte viele interessante neue Forschungsansätze und therapeutische Zielstrukturen. Dieser Übersichtsartikel fasst die Evidenz für eine zentrale Rolle von alpha-synuclein in der Pathogenese der PD zusammen, gefolgt von einer Diskussion neuer Therapiestrategien.


It took 180 years from James Parkinson’s descriptions in “An essay on the shaking palsy” to the discovery of alpha-synuclein as key player in Parkinson’s disease (PD). The identification of a PD causing mutation in the gene of alpha-synuclein was followed immediately by detection of its presence in Lewy bodies, inclusions found in the brains of patients. While many open questions remain, findings on how alpha-synuclein pathology emerges, propagates and causes neuronal death provide hope for development of disease-modifying therapeutics beyond the current dopamine replacement therapy. The recent hypothesis of a prion-like transmission of alpha-synuclein pathology raises controversy but also inspired numerous exciting research avenues, partially already translating into novel drug targets. This review summarizes evidence for a critical role of alpha-synuclein in PD pathogenesis followed by a discussion of current promising treatment avenues.

Keywords: synucleinopathy; prion; neurodegeneration; neuroprotection; dopamine


  • Alarcon-Aris D, Recasens A, Galofre M, Carballo-Carbajal I, Zacchi N, Ruiz-Bronchal E, Pavia-Collado R, Chica R, Ferres-Coy A, Santos M, Revilla R, Montefeltro A, Farinas I, Artigas F, Vila M, Bortolozzi A (2018) Selective alpha-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson’s Disease. Mol Ther 26:550–567.Google Scholar

  • Anwar S, Peters O, Millership S, Ninkina N, Doig N, Connor-Robson N, Threlfell S, Kooner G, Deacon RM, Bannerman DM, Bolam JP, Chandra SS, Cragg SJ, Wade-Martins R, Buchman VL (2011) Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family. J Neurosci 31,7264–7274.Google Scholar

  • Bendor JT, Logan TP, Edwards RH (2013) The function of alpha-synuclein. Neuron 79,1044–1066.Google Scholar

  • Berg D, Roggendorf W, Schroder U, Klein R, Tatschner T, Benz P, Tucha O, Preier M, Lange KW, Reiners K, Gerlach M, Becker G (2002) Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 59,999–1005.Google Scholar

  • Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24,197–211.Google Scholar

  • Burre J, Sharma M, Sudhof TC (2015) Definition of a molecular pathway mediating alpha-synuclein neurotoxicity. J Neurosci 35,5221–5232.Google Scholar

  • Carlsson A, Lindqvist M, Magnusson T (1957) 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180,1200.Google Scholar

  • Carlsson A, Lindqvist M, Magnusson T, Waldeck B (1958) On the presence of 3-hydroxytyramine in brain. Science 127,471.Google Scholar

  • Chesselet MF (2003) Dopamine and Parkinson’s disease: is the killer in the house? Mol Psychiatry 8,369–370.Google Scholar

  • Chesselet MF, Richter F (2011) Modelling of Parkinson’s disease in mice. Lancet Neurol 10,1108–1118.Google Scholar

  • Devine MJ, Gwinn K, Singleton A, Hardy J (2011) Parkinson’s disease and alpha-synuclein expression. Mov Disord 26,2160–2168.Google Scholar

  • Ehringer H, Hornykiewicz O (1960) [Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system]. Klin Wochenschr 38,1236–1239.Google Scholar

  • Gamez-Valero A, Beyer K, Borras FE (2019) Extracellular vesicles, new actors in the search for biomarkers of dementias. Neurobiol Aging 74,15–20.Google Scholar

  • Greffard S, Verny M, Bonnet AM, Seilhean D, Hauw JJ, Duyckaerts C (2010) A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol Aging 31,99–103.Google Scholar

  • Grundemann J, Schlaudraff F, Haeckel O, Liss B (2008) Elevated alpha-synuclein mRNA levels in individual UV-laser-microdissected dopaminergic substantia nigra neurons in idiopathic Parkinson’s disease. Nucleic acids research 36,e38.Google Scholar

  • Helmschrodt C, Hobel S, Schoniger S, Bauer A, Bonicelli J, Gringmuth M, Fietz SA, Aigner A, Richter A, Richter F (2017) Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce alpha-Synuclein Expression in a Model of Parkinson’s Disease. Molecular therapy Nucleic acids 9,57–68.Google Scholar

  • Jellinger KA, Korczyn AD (2018) Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease? BMC Med 16,34.Google Scholar

  • Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, Halliday GM, Bartus RT (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136,2419–2431.Google Scholar

  • Lazaro DF, Pavlou MAS, Outeiro TF (2017) Cellular models as tools for the study of the role of alpha-synuclein in Parkinson’s disease. Exp Neurol 298,162–171.Google Scholar

  • Levin J, Schmidt F, Boehm C, Prix C, Botzel K, Ryazanov S, Leonov A, Griesinger C, Giese A (2014) The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol 127,779–780.Google Scholar

  • Lewy F (1912) Paralysis agitans. In: Handbuch der Neurologie (Lewandowsky M AG, ed), pp 920–933. Berlin: Springer Verlag.Google Scholar

  • Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nature medicine 14,501–503.Google Scholar

  • Lionnet A, Leclair-Visonneau L, Neunlist M, Murayama S, Takao M, Adler CH, Derkinderen P, Beach TG (2018) Does Parkinson’s disease start in the gut? Acta Neuropathol 135,1–12.Google Scholar

  • Liu B, Fang F, Pedersen NL, Tillander A, Ludvigsson JF, Ekbom A, Svenningsson P, Chen H, Wirdefeldt K (2017) Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study. Neurology 88,1996–2002.Google Scholar

  • 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 338,949–953.Google Scholar

  • Malek N, Swallow D, Grosset KA, Anichtchik O, Spillantini M, Grosset DG (2014) Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson’s disease – a systematic review. Acta Neurol Scand 130,59–72.Google Scholar

  • Mao X et al. (2016) Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353.Google Scholar

  • Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, Patel MC, Spino M, Connelly J, Tricta F, Crichton RR, Dexter DT (2017) Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Sci Rep 7,1398.Google Scholar

  • McCormack AL, Mak SK, Henderson JM, Bumcrot D, Farrer MJ, Di Monte DA (2010) Alpha-synuclein suppression by targeted small interfering RNA in the primate substantia nigra. PLoS One 5,e12122.Google Scholar

  • Migdalska-Richards A, Ko WKD, Li Q, Bezard E, Schapira AHV (2017) Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse 71.Google Scholar

  • Mittal S et al. (2017) beta2-Adrenoreceptor is a regulator of the alpha-synuclein gene driving risk of Parkinson’s disease. Science 357,891–898.Google Scholar

  • Moors TE, Hoozemans JJ, Ingrassia A, Beccari T, Parnetti L, Chartier-Harlin MC, van de Berg WD (2017) Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease. Mol Neurodegener 12,11.Google Scholar

  • Ouchi Y, Yagi S, Yokokura M, Sakamoto M (2009) Neuroinflammation in the living brain of Parkinson’s disease. Parkinsonism Relat Disord 15 Suppl 3,S200–204.Google Scholar

  • Paciotti S, Bellomo G, Gatticchi L, Parnetti L (2018) Are We Ready for Detecting alpha-Synuclein Prone to Aggregation in Patients? The Case of “Protein-Misfolding Cyclic Amplification” and “Real-Time Quaking-Induced Conversion” as Diagnostic Tools. Frontiers in neurology 9,415.Google Scholar

  • Parkinson J (1817) An essay on the shaking palsy. Sherwood, Neely and Jones, London.Google Scholar

  • Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, Van den Haute C, Melki R, Baekelandt V (2015) alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522,340–344.Google Scholar

  • 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 276,2045–2047.Google Scholar

  • Recasens A, Carballo-Carbajal I, Parent A, Bove J, Gelpi E, Tolosa E, Vila M (2018) Lack of pathogenic potential of peripheral alpha-synuclein aggregates from Parkinson’s disease patients. Acta Neuropathol Commun 6,8.Google Scholar

  • Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A, Fernagut PO, Blesa J, Parent A, Perier C, Farinas I, Obeso JA, Bezard E, Vila M (2014) Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75,351–362.Google Scholar

  • Richter F, Subramaniam SR, Magen I, Lee P, Hayes J, Attar A, Zhu C, Franich NR, Bove N, De La Rosa K, Kwong J, Klarner FG, Schrader T, Chesselet MF, Bitan G (2017) A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing alpha-Synuclein. Neurotherapeutics 14,1107–1119.Google Scholar

  • Richter F, Fleming SM, Watson M, Lemesre V, Pellegrino L, Ranes B, Zhu C, Mortazavi F, Mulligan CK, Sioshansi PC, Hean S, De La Rosa K, Khanna R, Flanagan J, Lockhart DJ, Wustman BA, Clark SW, Chesselet MF (2014) A GCase chaperone improves motor function in a mouse model of synucleinopathy. Neurotherapeutics 11,840–856.Google Scholar

  • Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK (2016) Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 167,1469–1480 e1412.Google Scholar

  • Schapira AH, Olanow CW, Greenamyre JT, Bezard E (2014) Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: future therapeutic perspectives. Lancet 384,545–555.Google Scholar

  • Schon EA, Przedborski S (2011) Mitochondria: the next (neurode)generation. Neuron 70,1033–1053.Google Scholar

  • Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388,839–840.Google Scholar

  • Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sorensen HT (2015) Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 78,522–529.Google Scholar

  • Theillet FX, Binolfi A, Bekei B, Martorana A, Rose HM, Stuiver M, Verzini S, Lorenz D, van Rossum M, Goldfarb D, Selenko P (2016) Structural disorder of monomeric alpha-synuclein persists in mammalian cells. Nature 530,45–50.Google Scholar

  • Tretiakoff C (1919) Contribution a l’etude de l’anatomie pathologique du locus niger de Soemmering avec quelques deductions relatives a la pathogenie des troubles du tonus musculaire et de la maladie de Parkinson. These de Paris.Google Scholar

  • Tysnes OB, Kenborg L, Herlofson K, Steding-Jessen M, Horn A, Olsen JH, Reichmann H (2015) Does vagotomy reduce the risk of Parkinson’s disease? Ann Neurol 78,1011–1012.Google Scholar

  • Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH, Riek R (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 108,4194–4199.Google Scholar

  • Wrasidlo W et al. (2016) A de novo compound targeting alpha-synuclein improves deficits in models of Parkinson’s disease. Brain 139,3217–3236.Google Scholar

About the article

Prof. Dr. Franziska Richter Assêncio

Franziska Richter graduated 2007 in Veterinary Medicine (Dr. med. vet.) at the FU Berlin working on animal models of Parkinson´s disease. As a postdoc and research faculty in the lab of Marie-Francoise Chesselet, Department of Neurology at UCLA (2007–2012), she performed several preclinical trials in mouse models of alpha-synuclein pathology. In 2012 she joined Prof. Angelika Richter at the Faculty of Veterinary Medicine in Leipzig, extending her field to therapeutic interventions in dystonia. She is currently Professor and Chair of the Department of Pharmacology, Toxicology and Pharmacy at the University of Veterinary Medicine Hannover.

Published Online: 2019-06-04

Published in Print: 2019-05-27

Citation Information: Neuroforum, Volume 25, Issue 2, Pages 129–136, ISSN (Online) 2363-7013, ISSN (Print) 0947-0875, DOI: https://doi.org/10.1515/nf-2018-0029.

Export Citation

© 2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Comments (0)

Please log in or register to comment.
Log in