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Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane

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dc.contributor.author Pacheco, Carla R.
dc.contributor.author Morales, Camila N.
dc.contributor.author Ramírez, Alejandra E.
dc.contributor.author Muñoz López, Francisco José, 1964-
dc.contributor.author Gallegos, Scarlet S.
dc.contributor.author Caviedes, Pablo A.
dc.contributor.author Aguayo, Luis G.
dc.contributor.author Opazo, Carlos M.
dc.date.accessioned 2016-06-10T13:51:07Z
dc.date.available 2016-06-10T13:51:07Z
dc.date.issued 2015
dc.identifier.citation Pacheco CR, Morales CN, Ramírez AE, Muñoz FJ, Gallegos SS, Caviedes PA et al. Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane. Journal of Neurochemistry. 2015; 132(6): 731-741. DOI 10.1111/jnc.13060
dc.identifier.issn 0022-3042
dc.identifier.uri http://hdl.handle.net/10230/26902
dc.description.abstract It has been postulated that the accumulation of extracellular α-synuclein (α-syn) might alter the neuronal membrane by formation of 'pore-like structures' that will lead to alterations in ionic homeostasis. However, this has never been demonstrated to occur in brain neuronal plasma membranes. In this study, we show that α-syn oligomers rapidly associate with hippocampal membranes in a punctate fashion, resulting in increased membrane conductance (5 fold over control) and the influx of both calcium and a fluorescent glucose analogue. The enhancement in intracellular calcium (1.7 fold over control) caused a large increase in the frequency of synaptic transmission (2.5 fold over control), calcium transients (3 fold over control), and synaptic vesicle release. Both primary hippocampal and dissociated nigral neurons showed rapid increases in membrane conductance by α-syn oligomers. In addition, we show here that α-syn caused synaptotoxic failure associated with a decrease in SV2, a membrane protein of synaptic vesicles associated with neurotransmitter release. In conclusion, extracellular α-syn oligomers facilitate the perforation of the neuronal plasma membrane, thus explaining, in part, the synaptotoxicity observed in neurodegenerative diseases characterized by its extracellular accumulation. We propose that α-synuclein (α-syn) oligomers form pore-like structures in the plasma membrane of neurons from central nervous system (CNS). We believe that extracellular α-syn oligomers facilitate the formation of α-syn membrane pore-like structures, thus explaining, in part, the synaptotoxicity observed in neurodegenerative diseases characterized by its extracellular accumulation. We think that alterations in ionic homeostasis and synaptic vesicular depletion are key steps that lead to synaptotoxicity promoted by α -syn membrane pore-like structures.
dc.description.sponsorship C. R. Pacheco funded by Ph.D. fellowship from CONICYT and FEBS Scholarship. This work was supported by grant Anillo-PBCT ACT-04 from the Chilean Government (LGA, CO), FONDECYT grant No. 1100502 (LGA, CO), FONDECYT grant No. 1140473 (LGA) and Spanish Ministerio de Economía y Competitividad (FIS PI10/00587; ISCIII-RETIC RED HERACLES RD06/0009/002-FEDER), and La Marató de TV3 (No. 100310). The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof Journal of Neurochemistry. 2015; 132(6): 731-741
dc.rights This is the pre-peer reviewed version of the following article: Pacheco CR, Morales CN, Ramírez AE, Muñoz FJ, Gallegos SS, Caviedes PA et al. Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane. Journal of Neurochemistry. 2015; 132(6): 731-741. DOI 10.1111/jnc.13060, which has been published in final form at http://dx.doi.org/10.1111/jnc.13060. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
dc.subject.other Parkinson, Malaltia de
dc.title Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1111/jnc.13060
dc.subject.keyword Parkinson's disease
dc.subject.keyword Calcium
dc.subject.keyword Perforation
dc.subject.keyword Pore-like structures
dc.subject.keyword α-synuclein
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/acceptedVersion

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