Ca2+ is a key factor in α-synuclein-induced neurotoxicity

Plamena R. Angelova, Marthe H R Ludtmann, Mathew H. Horrocks, Alexander Negoda, Nunilo Cremades, David Klenerman, Christopher M. Dobson, Nicholas W. Wood, Evgeny Pavlov, Sonia Gandhi, Andrey Y. Abramov

Research output: Contribution to journalArticle

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 Ca2+ 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 Ca2+ 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 a- synuclein to affect Ca2+ 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 Ca2+, which prevented the α-synuclein-induced Ca2+ dysregulation. The findings of this study confirm that α-synuclein interacts with membranes to affect Ca2+ signalling in a structure-specific manner and the oligomeric β-sheetrich α-synuclein species ultimately leads to Ca2+ dysregulation and Ca2+-dependent cell death.

Original languageEnglish (US)
Pages (from-to)1792-1801
Number of pages10
JournalJournal of Cell Science
Volume129
Issue number9
DOIs
StatePublished - May 1 2016

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Synucleins
Artificial Membranes
Cell Death
Electrophysiology
Membranes
Astrocytes
Parkinson Disease

Keywords

  • Ca signalling
  • Neuronal death
  • Parkinson's disease
  • α-Synuclein

ASJC Scopus subject areas

  • Cell Biology

Cite this

Angelova, P. R., Ludtmann, M. H. R., Horrocks, M. H., Negoda, A., Cremades, N., Klenerman, D., ... Abramov, A. Y. (2016). Ca2+ is a key factor in α-synuclein-induced neurotoxicity. Journal of Cell Science, 129(9), 1792-1801. https://doi.org/10.1242/jcs.180737

Ca2+ is a key factor in α-synuclein-induced neurotoxicity. / Angelova, Plamena R.; Ludtmann, Marthe H R; Horrocks, Mathew H.; Negoda, Alexander; Cremades, Nunilo; Klenerman, David; Dobson, Christopher M.; Wood, Nicholas W.; Pavlov, Evgeny; Gandhi, Sonia; Abramov, Andrey Y.

In: Journal of Cell Science, Vol. 129, No. 9, 01.05.2016, p. 1792-1801.

Research output: Contribution to journalArticle

Angelova, PR, Ludtmann, MHR, Horrocks, MH, Negoda, A, Cremades, N, Klenerman, D, Dobson, CM, Wood, NW, Pavlov, E, Gandhi, S & Abramov, AY 2016, 'Ca2+ is a key factor in α-synuclein-induced neurotoxicity', Journal of Cell Science, vol. 129, no. 9, pp. 1792-1801. https://doi.org/10.1242/jcs.180737
Angelova PR, Ludtmann MHR, Horrocks MH, Negoda A, Cremades N, Klenerman D et al. Ca2+ is a key factor in α-synuclein-induced neurotoxicity. Journal of Cell Science. 2016 May 1;129(9):1792-1801. https://doi.org/10.1242/jcs.180737
Angelova, Plamena R. ; Ludtmann, Marthe H R ; Horrocks, Mathew H. ; Negoda, Alexander ; Cremades, Nunilo ; Klenerman, David ; Dobson, Christopher M. ; Wood, Nicholas W. ; Pavlov, Evgeny ; Gandhi, Sonia ; Abramov, Andrey Y. / Ca2+ is a key factor in α-synuclein-induced neurotoxicity. In: Journal of Cell Science. 2016 ; Vol. 129, No. 9. pp. 1792-1801.
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