title: Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease.
abstract: OBJECTIVE
  Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death remains unknown. In this study, we describe how aggregation of alpha-synuclein (α-S) from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity.
  
  
  RESULTS
  We first demonstrate excessive free radical production in a human induced pluripotent stem-derived α-S triplication model at basal levels and on application of picomolar doses of β-sheet-rich α-S oligomers. We probed the effects of different structural species of α-S in wild-type rat neuronal cultures and show that both oligomeric and fibrillar forms of α-S are capable of generating free radical production, but that only the oligomeric form results in reduction of endogenous glutathione and subsequent neuronal toxicity. We dissected the mechanism of oligomer-induced free radical production and found that it was interestingly independent of several known cellular enzymatic sources.
  
  
  METHODS
  The oligomer-induced reactive oxygen species (ROS) production was entirely dependent on the presence of free metal ions as addition of metal chelators was able to block oligomer-induced ROS production and prevent oligomer-induced neuronal death.
  
  
  CONCLUSIONS
  Our findings further support the causative role of soluble amyloid oligomers in triggering neurodegeneration and shed light into the mechanisms by which these species cause neuronal damage, which, we show here, can be amenable to modulation through the use of metal chelation.
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Emma
authors.initials: E
authors.lastname: Deas
authors.affiliation: 2 Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge, United Kingdom .
authors.forename: Nunilo
authors.initials: N
authors.lastname: Cremades
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Plamena R
authors.initials: PR
authors.lastname: Angelova
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Marthe H R
authors.initials: MH
authors.lastname: Ludtmann
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .|3 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.affiliation: 2 Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge, United Kingdom .
authors.forename: Serene
authors.initials: S
authors.lastname: Chen
authors.affiliation: 2 Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge, United Kingdom .
authors.forename: Mathew H
authors.initials: MH
authors.lastname: Horrocks
authors.affiliation: 4 MRC Laboratory for Molecular Cell Biology, UCL , London, United Kingdom .
authors.forename: Blerida
authors.initials: B
authors.lastname: Banushi
authors.affiliation: 4 MRC Laboratory for Molecular Cell Biology, UCL , London, United Kingdom .
authors.forename: Daniel
authors.initials: D
authors.lastname: Little
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Devine
authors.affiliation: 4 MRC Laboratory for Molecular Cell Biology, UCL , London, United Kingdom .
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.affiliation: 2 Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge, United Kingdom .
authors.forename: David
authors.initials: D
authors.lastname: Klenerman
authors.affiliation: 2 Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge, United Kingdom .
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .|3 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Sonia
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom .
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002454:Cell Differentiation; D004789:Enzyme Activation; D020440:Gene Duplication; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007477:Ions / Q000378:metabolism*; D008670:Metals / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation; D055503:Protein Multimerization; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D007477:Ions; D008670:Metals; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D053148:Caspase 3; D053179:Caspase 7; D005978:Glutathione