title: Ca2+ is a key factor in α-synuclein-induced neurotoxicity.
abstract: Aggregation of α-synuclein leads to the formation of oligomeric intermediates that can interact with membranes to form pores. However, it is unknown how this leads to cell toxicity in Parkinson's disease. We investigated the species-specific effects of α-synuclein on Ca(2+) signalling in primary neurons and astrocytes using live neuronal imaging and electrophysiology on artificial membranes. We demonstrate that α-synuclein induces an increase in basal intracellular Ca(2+) in its unfolded monomeric state as well as in its oligomeric state. Electrophysiology of artificial membranes demonstrated that α-synuclein monomers induce irregular ionic currents, whereas α-synuclein oligomers induce rare discrete channel formation events. Despite the ability of monomeric α-synuclein to affect Ca(2+) signalling, it is only the oligomeric form of α-synuclein that induces cell death. Oligomer-induced cell death was abolished by the exclusion of extracellular Ca(2+), which prevented the α-synuclein-induced Ca(2+) dysregulation. The findings of this study confirm that α-synuclein interacts with membranes to affect Ca(2+) signalling in a structure-specific manner and the oligomeric β-sheet-rich α-synuclein species ultimately leads to Ca(2+) dysregulation and Ca(2+)-dependent cell death.
authors.affiliation: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Plamena R
authors.initials: PR
authors.lastname: Angelova
authors.affiliation: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Marthe H R
authors.initials: MH
authors.lastname: Ludtmann
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Mathew H
authors.initials: MH
authors.lastname: Horrocks
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax B3H 4R2, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Negoda
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Nunilo
authors.initials: N
authors.lastname: Cremades
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: David
authors.initials: D
authors.lastname: Klenerman
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax B3H 4R2, Canada College of Dentistry, New York University, New York 10010, USA.
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Pavlov
authors.affiliation: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK a.abramov@ucl.ac.uk sonia.gandhi@ucl.ac.uk.
authors.forename: Sonia
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK a.abramov@ucl.ac.uk sonia.gandhi@ucl.ac.uk.
authors.forename: Andrey Y
authors.identifier: 0000-0002-7646-7235
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D016923:Cell Death; D002478:Cells, Cultured; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D055503:Protein Multimerization / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497606:Snca protein, rat; D051844:alpha-Synuclein; D002118:Calcium
keywords: Ca2+ signalling; Neuronal death; Parkinson's disease; α-Synuclein