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

Angelova, P.R. ; Ludtmann, M.H.R. ; Horrocks, M.H. ; Negoda, A. ; Cremades, N. (Universidad de Zaragoza) ; Klenerman, D. ; Dobson, C.M. ; Wood, N.W. ; Pavlov, E.V. ; Gandhi, S. ; Abramov, A.Y.

Resumen: 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 α-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-sheet-rich α-synuclein species ultimately leads to Ca2+ dysregulation and Ca2+-dependent cell death.

Idioma: Inglés

DOI: 10.1242/jcs.180737

Año: 2016

Publicado en: JOURNAL OF CELL SCIENCE 129, 9 (2016), 1792-1801
ISSN: 0021-9533

Factor impacto JCR: 4.431 (2016)

Categ. JCR: CELL BIOLOGY rank: 61 / 189 = 0.323 (2016) - Q2 - T1

Factor impacto SCIMAGO: 3.12 - Cell Biology (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)