Abstract
Current therapies for Parkinson’s disease (PD) confer symptomatic relief and are particularly efficient in the treatment of motor symptoms in earlier disease stages. However, we are still unable to treat the causes of neurodegeneration by modification of the underlying mechanisms, which is partially due to their insufficient understanding. In this short review, we focus on two pivotal disease mechanisms: alpha-synuclein pathology and dysfunction of iron homeostasis as well as their intricate interaction. Both pathomechanisms have been extensively studied in the past and represent valid targets for disease-modifying pharmacological treatment approaches for PD. We summarize the current attempts to exploit iron chelation and modification of alpha-synuclein pathology as translational therapies in PD and discuss the chances and challenges of prospective disease-modifying approaches.
Similar content being viewed by others
References
Acosta-Cabronero J, Cardenas-Blanco A, Betts MJ et al. (2016) The whole-brain pattern of magnetic susceptibility perturbations in Parkinson’s disease. Brain 140(1):118–131. doi:10.1093/brain/aww278
Affiris (2016) Boost vaccination data encourage continued development of AFFiRiS therapeutic Parkinson’s disease vaccine against alpha-synuclein |Affiris| bringing vaccines to chronic disease. http://www.affiris.com/news/boost-vaccination-data-encourage-continued-development-of-affiris-therapeutic-parkinsons-disease-vaccine-against-alpha-synuclein/. Accessed 23 Dec 2016
Anderson JP, Walker DE, Goldstein JM et al (2006) Phosphorylation of Ser-129 Is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752. doi:10.1074/jbc.M600933200
Anderson CP, Shen M, Eisenstein RS, Leibold EA (2012) Mammalian iron metabolism and its control by iron regulatory proteins. BBA Mol Cell Res 1823:1468–1483. doi:10.1016/j.bbamcr.2012.05.010
Angot EE, Steiner JA, Hansen C et al (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9:1128–1138. doi:10.1016/S1474-4422(10)70213-1
Beekes M, Thomzig A, Schulz-Schaeffer WJ, Burger R (2014) Is there a risk of prion-like disease transmission by Alzheimer- or Parkinson-associated protein particles? Acta Neuropathol 128:463–476. doi:10.1007/s00401-014-1324-9
Bergström A-L, Kallunki P, Fog K (2015) Development of passive immunotherapies for synucleinopathies. Mov Disord 31:203–213. doi:10.1002/mds.26481
Bhullar KS, Rupasinghe HPV (2013) Polyphenols: multipotent therapeutic agents in neurodegenerative diseases. Oxid Med Cell Longev 2013:1–18. doi:10.1155/2013/891748
Binolfi AES, Rasia RM, Bertoncini CW et al (2006) Interaction of alpha-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement. J Am Chem Soc 128:9893–9901. doi:10.1021/ja0618649
Boddaert N, Le Quan Sang KH, Rötig A et al (2007) Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 110:401–408. doi:10.1182/blood-2006-12-065433
Bohic S, Murphy K, Paulus W et al (2008) Intracellular chemical imaging of the developmental phases of human neuromelanin using synchrotron X-ray microspectroscopy. Anal Chem 80:9557–9566. doi:10.1021/ac801817k
Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211
Cabantchik ZI, Munnich A, Youdim MB, Devos D (2013) Regional siderosis: a new challenge for iron chelation therapy. Front Pharmacol 4:167. doi:10.3389/fphar.2013.00167
Caruana M, Högen T, Levin J et al (2011) Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds. FEBS Lett 585:1113–1120. doi:10.1016/j.febslet.2011.03.046
Cummings J, Isaacson S, Mills R et al (2014) Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383:533–540. doi:10.1016/S0140-6736(13)62106-6
Davies P, Moualla D, Brown DR (2011) Alpha-synuclein is a cellular ferrireductase. PLoS One 6:e15814. doi:10.1371/journal.pone.0015814
De Rosa P, Marini ES, Gelmetti V, Valente EM (2015) Candidate genes for Parkinson disease: lessons from pathogenesis. Clin Chim Acta 449:68–76. doi:10.1016/j.cca.2015.04.042
Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H (2010) Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol 119:703–713. doi:10.1007/s00401-010-0665-2
Devos D, Moreau C, Devedjian JC et al (2014) Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 21:195–210. doi:10.1089/ars.2013.5593
Dexter D, Carayon A, Javoy-Agid F et al (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114:1953–1975
Double KL, Gerlach M, Schünemann V et al (2003) Iron-binding characteristics of neuromelanin of the human substantia nigra. Biochem Pharmacol 66:489–494. doi:10.1016/S0006-2952(03)00293-4
Ducić T, Carboni E, Lai B et al (2015) Alpha-synuclein regulates neuronal levels of manganese and calcium. ACS Chem Neurosci 6:1769–1779. doi:10.1021/acschemneuro.5b00093
Dufty BM, Warner LR, Hou ST et al (2007) Calpain-cleavage of alpha-synuclein: connecting proteolytic processing to disease-linked aggregation. Am J Pathol 170:1725–1738. doi:10.2353/ajpath.2007.061232
Earle KM (1968) Studies on Parkinson’s disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27:1–14
Finkelstein DI, Hare DJ, Billings JL et al. (2016) The metal chelator clioquinol improves cognitive, motor function and micro-anatomy of the alpha-synuclein hA53T transgenic mice. ACS Chem Neurosci 7(1):119–129. doi:10.1021/acschemneuro.5b00253
Galvin JE (2006) Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson’s disease: a case for the selective vulnerability of the substantia nigra. Acta Neuropathol 112:115–126. doi:10.1007/s00401-006-0096-2
Gasser T, Hardy J, Mizuno Y (2011) Milestones in PD genetics. Mov Disord 26:1042–1048. doi:10.1002/mds.23637
Gilman S, Koller M, Black RS et al (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–1562. doi:10.1212/01.WNL.0000159740.16984.3C
Guo JL, Lee VMY (2014) Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 20:130–138. doi:10.1038/nm.3457
Halliday GM, Holton JL, Revesz T, Dickson DW (2011) Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122:187–204. doi:10.1007/s00401-011-0852-9
Hare DJ, Double KL (2016) Iron and dopamine: a toxic couple. Brain 139:1026–1035. doi:10.1093/brain/aww022
Hauser RA, Heritier S, Rowse GJ et al (2016) Droxidopa and reduced falls in a trial of Parkinson disease patients with neurogenic orthostatic hypotension. Clin Neuropharmacol 39:220–226. doi:10.1097/WNF.0000000000000168
Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614. doi:10.1111/j.1365-2990.2007.00874.x
He N, Ling H, Ding B et al (2015) Region-specific disturbed iron distribution in early idiopathic Parkinson’s disease measured by quantitative susceptibility mapping. Hum Brain Mapp 36:4407–4420. doi:10.1002/hbm.22928
Hebron ML, Lonskaya I, Moussa CE-H (2013) Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models. Hum Mol Genet 22:3315–3328. doi:10.1093/hmg/ddt192
Holmes BB, DeVos SL, Kfoury N et al (2013) Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci USA 110:E3138–E3147. doi:10.1073/pnas.1301440110
Inden M, Kitamura Y, Takeuchi H et al (2007) Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. J Neurochem 101:1491–1504. doi:10.1111/j.1471-4159.2006.04440.x
Irwin DJ, Abrams JY, Schonberger LB et al (2013) Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol 70:462–467. doi:10.1001/jamaneurol.2013.1933
Kostka M, Högen T, Danzer KM et al (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283:10992–11003. doi:10.1074/jbc.M709634200
Levin J, Högen T, Hillmer AS et al (2011) Generation of ferric iron links oxidative stress to α-synuclein oligomer formation. J Parkinsons Dis 1:205–216. doi:10.3233/JPD-2011-11040
Levin J, Schmidt F, Boehm C et al (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. doi:10.1007/s00401-014-1265-3
Levin J, Maaß S, Schuberth M et al (2016) The PROMESA-protocol: progression rate of multiple system atrophy under EGCG supplementation as anti-aggregation-approach. J Neural Transm 123:439–445. doi:10.1007/s00702-016-1507-8
Lewy FH (1912) Paralysis agitans. I. Pathologische anatomie. Handbuch der neurologie
Lhermitte J, Kraus WM, McAlpine D (1924) Original papers: on the occurrence of abnormal deposits of iron in the brain in Parkinsonism with special reference to its localisation. J Neurol Psychopathol 5:195
Li W, West N, Colla E et al (2005) Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci USA 102:2162–2167. doi:10.1073/pnas.0406976102
Li J-Y, Englund E, Holton JL et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503. doi:10.1038/nm1746
Li W, Englund E, Widner H et al (2016) Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci USA 113:6544–6549. doi:10.1073/pnas.1605245113
Lu Y, Prudent M, Fauvet B et al (2011) Phosphorylation of α-synuclein at Y125 and S129 alters its metal binding properties: implications for understanding the role of α-synuclein in the pathogenesis of Parkinson’s disease and related disorders. ACS Chem Neurosci 2:667–675. doi:10.1021/cn200074d
Luk KC, Kehm V, Carroll J et al (2012) Pathological-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953. doi:10.1126/science.1227157
Mandler M, Valera E, Rockenstein E et al (2014) Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol 127:861–879. doi:10.1007/s00401-014-1256-4
Mao X, Schimmer AD (2008) The toxicology of Clioquinol. Toxicol Lett 182:1–6. doi:10.1016/j.toxlet.2008.08.015
Mao X, Ou MT, Karuppagounder SS et al (2016) Pathological -synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353(6307):aah3374. doi:10.1126/science.aah3374
Martin-Bastida A, Lao-Kaim NP, Loane C et al (2017) Motor associations of iron accumulation in deep grey matter nuclei in Parkinson’s disease: a cross-sectional study of iron-related magnetic resonance imaging susceptibility. Eur J Neurol 24(2):357–365. doi:10.1111/ene.13208
Masliah E, Rockenstein E, Mante M et al (2011) Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One 6(4):e19338-17. doi:10.1371/journal.pone.0019338
Masuda-Suzukake M, Nonaka T, Hosokawa M et al (2014) Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol Commun 2:88. doi:10.1186/s40478-014-0088-8
Mills E, Dong X-P, Wang F, Xu H (2010) Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. Future Med Chem 2:51–64. doi:10.1021/ac901991x
Oertel W, Schulz JB (2016) Current and experimental treatments of Parkinson disease: a guide for neuroscientists. J Neurochem 139(Suppl 1):325–337. doi:10.1111/jnc.13750
Ortega R, Carmona A, Roudeau S et al (2016) α-Synuclein over-expression induces increased iron accumulation and redistribution in iron-exposed neurons. Mol Neurobiol 53(3):1925–1934. doi:10.1007/s12035-015-9146-x
Ostrerova-Golts N, Petrucelli L, Hardy J et al (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054
Pagan F, Hebron M, Valadez EH et al (2016) Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis 6:503–517. doi:10.3233/JPD-160867
Pan-Montojo F, Schwarz M, Winkler C et al (2012) Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep 2:1–12. doi:10.1038/srep00898
Paumier KL, Luk KC, Manfredsson FP et al (2015) Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185–199. doi:10.1016/j.nbd.2015.06.003
Peelaerts W, Bousset L, Van der Perren A et al (2015) α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344. doi:10.1038/nature14547
Peng Y, Wang C, Xu HH et al (2010) Binding of alpha-synuclein with Fe(III) and with Fe(II) and biological implications of the resultant complexes. J Inorg Biochem 104:365–370. doi:10.1016/j.jinorgbio.2009.11.005
Polymeropoulos MHM, Lavedan CC, Leroy EE et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047
Rasia RMR, Bertoncini CWC, Marsh DD et al (2005) Structural characterization of copper(II) binding to alpha-synuclein: insights into the bioinorganic chemistry of Parkinson’s disease. Proc Natl Acad Sci USA 102:4294–4299. doi:10.1073/pnas.0407881102
Rodriguez JA, Ivanova MI, Sawaya MR et al (2015) Structure of the toxic core of α-synuclein from invisible crystals. Nature 525:486–490. doi:10.1038/nature15368
Ryan P, Hynes MJ (2007) The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron(III). J Inorg Biochem 101:585–593. doi:10.1016/j.jinorgbio.2006.12.001
Salazar J, Mena N, Hunot S et al (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci USA 105:18578–18583. doi:10.1073/pnas.0804373105
Sauerbier A, Qamar MA, Rajah T, Chaudhuri KR (2016) New concepts in the pathogenesis and presentation of Parkinson’s disease. Clin Med 16:365–370. doi:10.7861/clinmedicine.16-4-365
Schneeberger A, Tierney L, Mandler M (2015) Active immunization therapies for Parkinson’s disease and multiple system atrophy. Mov Disord 31:214–224. doi:10.1002/mds.26377
Sigel A, Sigel H, Sigel RKO (2006) Neurodegenerative diseases and metal ions. Wiley, Chichester
Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. doi:10.1038/42166
Svensson E, Horváth-Puhó E, Thomsen RW et al (2015) Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 78:522–529. doi:10.1002/ana.24448
Tatenhorst L, Eckermann K, Dambeck V et al (2016) Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease. Acta Neuropathol Commun 4:39. doi:10.1186/s40478-016-0310-y
Todorich B, Pasquini JM, Garcia CI et al (2009) Oligodendrocytes and myelination: the role of iron. Glia 57:467–478. doi:10.1002/glia.20784
Trétiakoff C (1919) Contribution à l“étude de l”anatomie pathologique du locus niger de Soemmering avec quelques déductions relatives à la pathogénie des troubles du tonus musculaire et de la maladie de Parkinson
Tuttle MD, Comellas G, Nieuwkoop AJ et al (2016) Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nat Struct Mol Biol 23:409–415. doi:10.1038/nsmb.3194
Uversky VN, Li J, Fink AL (2001) Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson’s disease and heavy metal exposure. J Biol Chem 276:44284–44296. doi:10.1074/jbc.M105343200
Wagner J, Ryazanov S, Leonov A et al (2013) Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol. doi:10.1007/s00401-013-1114-9
Wakabayashi K, Takahashi H, Takeda S et al (1988) Parkinson’s disease: the presence of Lewy bodies in Auerbach‘s and Meissner’s plexuses. Acta Neuropathol 76:217–221
Walsh DM, Selkoe DJ (2016) A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci 17:251–260. doi:10.1038/nrn.2016.13
Wang J-Y, Zhuang Q-Q, Zhu L-B et al (2016) Meta-analysis of brain iron levels of Parkinson’s disease patients determined by postmortem and MRI measurements. Sci Rep 6:36669. doi:10.1038/srep36669
Weinreb O, Mandel S, Youdim MBH, Amit T (2013) Targeting dysregulation of brain iron homeostasis in Parkinson’s disease by iron chelators. Free Radic Biol Med 62:52–64. doi:10.1016/j.freeradbiomed.2013.01.017
Wyse RK, Brundin P, Sherer TB (2016) Nilotinib—differentiating the Hope from the Hype. J Parkinsons Dis 6:519–522. doi:10.3233/JPD-160904
Zecca L, Youdim MBH, Riederer P et al (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873. doi:10.1038/nrn1537
Zucca FA, Segura-Aguilar J, Ferrari E et al (2015) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. doi:10.1016/j.pneurobio.2015.09.012
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lingor, P., Carboni, E. & Koch, J.C. Alpha-synuclein and iron: two keys unlocking Parkinson’s disease. J Neural Transm 124, 973–981 (2017). https://doi.org/10.1007/s00702-017-1695-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-017-1695-x