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Published in: Journal of Neural Transmission 8/2017

01-08-2017 | Translational Neurosciences - Review Article

Alpha-synuclein and iron: two keys unlocking Parkinson’s disease

Authors: Paul Lingor, Eleonora Carboni, Jan Christoph Koch

Published in: Journal of Neural Transmission | Issue 8/2017

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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.
Literature
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefPubMed Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefPubMed
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference 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 114:1953–1975CrossRefPubMed 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 114:1953–1975CrossRefPubMed
go back to reference Earle KM (1968) Studies on Parkinson’s disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27:1–14CrossRefPubMed Earle KM (1968) Studies on Parkinson’s disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27:1–14CrossRefPubMed
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference Lewy FH (1912) Paralysis agitans. I. Pathologische anatomie. Handbuch der neurologie Lewy FH (1912) Paralysis agitans. I. Pathologische anatomie. Handbuch der neurologie
go back to reference 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 5:195CrossRefPubMedPubMedCentral 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 5:195CrossRefPubMedPubMedCentral
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference Ostrerova-Golts N, Petrucelli L, Hardy J et al (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054PubMed Ostrerova-Golts N, Petrucelli L, Hardy J et al (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054PubMed
go back to reference 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 CrossRef 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 CrossRef
go back to reference Polymeropoulos MHM, Lavedan CC, Leroy EE et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047CrossRefPubMed Polymeropoulos MHM, Lavedan CC, Leroy EE et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047CrossRefPubMed
go back to reference Sigel A, Sigel H, Sigel RKO (2006) Neurodegenerative diseases and metal ions. Wiley, ChichesterCrossRef Sigel A, Sigel H, Sigel RKO (2006) Neurodegenerative diseases and metal ions. Wiley, ChichesterCrossRef
go back to reference 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 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
go back to reference 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 CrossRefPubMed 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 CrossRefPubMed
go back to reference 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 76:217–221CrossRefPubMed 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 76:217–221CrossRefPubMed
Metadata
Title
Alpha-synuclein and iron: two keys unlocking Parkinson’s disease
Authors
Paul Lingor
Eleonora Carboni
Jan Christoph Koch
Publication date
01-08-2017
Publisher
Springer Vienna
Published in
Journal of Neural Transmission / Issue 8/2017
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI
https://doi.org/10.1007/s00702-017-1695-x

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