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.ca
• dc.contributor.author Morales, Camila N.ca
• dc.contributor.author Ramírez, Alejandra E.ca
• dc.contributor.author Muñoz López, Francisco José, 1964-ca
• dc.contributor.author Gallegos, Scarlet S.ca
• dc.contributor.author Caviedes, Pablo A.ca
• dc.contributor.author Aguayo, Luis G.ca
• dc.contributor.author Opazo, Carlos M.ca
• dc.date.accessioned 2016-06-10T13:51:07Z
• dc.date.available 2016-06-10T13:51:07Z
• dc.date.issued 2015
• 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.ca
• 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/pdfca
• 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.13060ca
• dc.identifier.doi http://dx.doi.org/10.1111/jnc.13060
• dc.identifier.issn 0022-3042
• dc.identifier.uri http://hdl.handle.net/10230/26902
• dc.language.iso engca
• dc.publisher Wileyca
• 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.ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• 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.subject.other Parkinson, Malaltia deca
• dc.title Extracellular α-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membraneca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca