title: α-Synuclein Over-Expression Induces Increased Iron Accumulation and Redistribution in Iron-Exposed Neurons.
abstract: Parkinson's disease is the most common α-synucleinopathy, and increased levels of iron are found in the substantia nigra of Parkinson's disease patients, but the potential interlink between both molecular changes has not been fully understood. Metal to protein binding assays have shown that α-synuclein can bind iron in vitro; therefore, we hypothesized that iron content and iron distribution could be modified in cellulo, in cells over-expressing α-synuclein. Owing to particle-induced X-ray emission and synchrotron X-ray fluorescence chemical nano-imaging, we were able to quantify and describe the iron distribution at the subcellular level. We show that, in neurons exposed to excess iron, the mere over-expression of human α-synuclein results in increased levels of intracellular iron and in iron redistribution from the cytoplasm to the perinuclear region within α-synuclein-rich inclusions. Reproducible results were obtained in two distinct recombinant expression systems, in primary rat midbrain neurons and in a rat neuroblastic cell line (PC12), both infected with viral vectors expressing human α-synuclein. Our results link two characteristic molecular features found in Parkinson's disease, the accumulation of α-synuclein and the increased levels of iron in the substantia nigra.
authors.affiliation: University of Bordeaux, CENBG, UMR 5797, 33170, Gradignan, France. ortega@cenbg.in2p3.fr.|CNRS, IN2P3, CENBG, UMR 5797, 33170, Gradignan, France. ortega@cenbg.in2p3.fr.
authors.forename: Richard
authors.initials: R
authors.lastname: Ortega
authors.affiliation: University of Bordeaux, CENBG, UMR 5797, 33170, Gradignan, France.|CNRS, IN2P3, CENBG, UMR 5797, 33170, Gradignan, France.
authors.forename: Asuncion
authors.initials: A
authors.lastname: Carmona
authors.affiliation: University of Bordeaux, CENBG, UMR 5797, 33170, Gradignan, France.|CNRS, IN2P3, CENBG, UMR 5797, 33170, Gradignan, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Roudeau
authors.affiliation: University of Bordeaux, CENBG, UMR 5797, 33170, Gradignan, France.|CNRS, IN2P3, CENBG, UMR 5797, 33170, Gradignan, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Perrin
authors.affiliation: CELLS-ALBA, Carretera, BP 1413, 08290, Cerdanyola del Vallès, Barcelona, Spain.
authors.forename: Tanja
authors.initials: T
authors.lastname: Dučić
authors.affiliation: Department of Neurology, University of Medicine, 37075, Göttingen, Germany.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Carboni
authors.affiliation: INSERM U-836 Team 6, Rayonnement Synchrotron et Recherche Médicale, 38043, Grenoble, France.|European Synchrotron Radiation Facility (ESRF), X-ray Imaging Group, 38043, Grenoble, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bohic
authors.affiliation: European Synchrotron Radiation Facility (ESRF), X-ray Imaging Group, 38043, Grenoble, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Cloetens
authors.affiliation: Department of Neurology, University of Medicine, 37075, Göttingen, Germany. plingor@gwdg.de.|DFG-Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany. plingor@gwdg.de.
authors.forename: Paul
authors.initials: P
authors.lastname: Lingor
mesh_terms: D000818:Animals; D002452:Cell Count; D048429:Cell Size; D005822:Genetic Vectors / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D036103:Nanotechnology; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D013052:Spectrometry, X-Ray Emission; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; D007501:Iron
keywords: Iron; Neuroimaging; Parkinson’s disease; Synchrotron; α-Synuclein
references.citation: Mov Disord. 1999 May;14(3):417-22
references.pmid: 10348463
references.citation: J Neurochem. 1991 Feb;56(2):446-51
references.pmid: 1988548
references.citation: Anal Bioanal Chem. 2008 Mar;390(6):1585-94
references.pmid: 18246461
references.citation: Biochem Biophys Res Commun. 2009 Mar 6;380(2):377-81
references.pmid: 19250637
references.citation: Neurobiol Dis. 2010 Jun;38(3):395-404
references.pmid: 20211260
references.citation: J Inorg Biochem. 2010 Apr;104(4):365-70
references.pmid: 20005574
references.citation: Cell Death Differ. 2013 Mar;20(3):465-77
references.pmid: 23154387
references.citation: J Biol Chem. 2008 Apr 18;283(16):10992-1003
references.pmid: 18258594
references.citation: J Neurosci. 2000 Aug 15;20(16):6048-54
references.pmid: 10934254
references.citation: Neurosci Bull. 2010 Jun;26(3):205-10
references.pmid: 20502498
references.citation: Mov Disord. 2011 Oct;26(12):2160-8
references.pmid: 21887711
references.citation: Neurology. 2004 May 25;62(10):1835-8
references.pmid: 15159488
references.citation: Acta Neuropathol. 2000 Aug;100(2):111-4
references.pmid: 10963356
references.citation: J Biol Chem. 2002 Feb 15;277(7):5411-7
references.pmid: 11724769
references.citation: Neuroreport. 2012 Jun 20;23(9):576-80
references.pmid: 22581044
references.citation: J Biol Chem. 2002 May 3;277(18):16116-23
references.pmid: 11850416
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):2015-24
references.pmid: 19460457
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4294-9
references.pmid: 15767574
references.citation: Acta Neuropathol. 2012 May;123(5):671-83
references.pmid: 22167382
references.citation: Neuroscience. 2001;104(3):901-12
references.pmid: 11440819
references.citation: Mol Psychiatry. 2007 Mar;12(3):222-3
references.pmid: 17325711
references.citation: Science. 1997 Jun 27;276(5321):2045-7
references.pmid: 9197268
references.citation: Nat Methods. 2012 Jul;9(7):671-5
references.pmid: 22930834
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12564-9
references.pmid: 20538976
references.citation: J R Soc Interface. 2009 Oct 6;6 Suppl 5:S649-58
references.pmid: 19605403
references.citation: Biochem Biophys Res Commun. 2007 Jul 20;359(1):115-20
references.pmid: 17531952
references.citation: Eur J Epidemiol. 2011 Jun;26 Suppl 1:S1-58
references.pmid: 21626386
references.citation: Neurosci Lett. 2014 May 21;569:27-32
references.pmid: 24670480
references.citation: Front Pharmacol. 2014 Apr 21;5:81
references.pmid: 24795635
references.citation: J Neural Transm (Vienna). 2011 Aug;118(8):1165-72
references.pmid: 21336954
references.citation: J Am Chem Soc. 2006 Aug 2;128(30):9893-901
references.pmid: 16866548
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10907-12
references.pmid: 18669654
references.citation: Cell Death Dis. 2014 May 15;5:e1225
references.pmid: 24832597
references.citation: Neurobiol Dis. 2015 Jan;73:150-62
references.pmid: 25283984
references.citation: J Neurochem. 2013 Jan;124(2):250-61
references.pmid: 23106162
references.citation: J Neural Transm (Vienna). 2011 Mar;118(3):397-406
references.pmid: 20690031
references.citation: Nature. 1997 Aug 28;388(6645):839-40
references.pmid: 9278044
references.citation: Histochem Cell Biol. 2013 May;139(5):671-84
references.pmid: 23212845
references.citation: Toxicol In Vitro. 1995 Aug;9(4):365-8
references.pmid: 20650100
references.citation: PLoS One. 2012;7(4):e36377
references.pmid: 22558453
references.citation: Anal Bioanal Chem. 2014 Nov;406(27):6979-91
references.pmid: 25023971
references.citation: Neuron. 2009 Apr 30;62(2):218-29
references.pmid: 19409267
references.citation: FEBS J. 2011 Sep;278(18):3472-83
references.pmid: 21790997
references.citation: PLoS One. 2011 Jan 10;6(1):e15814
references.pmid: 21249223
references.citation: Exp Neurol. 2000 May;163(1):55-62
references.pmid: 10785444
references.citation: Biochem Biophys Res Commun. 2010 Jan 1;391(1):461-6
references.pmid: 19914207