Extracellular alpha-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane
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2015Metadata
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Pacheco, Carla R.
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Extracellular alpha-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane
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Abstract
It has been postulated that the accumulation of extracellular alpha-synuclein (alpha-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 a-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 a-syn oligomers. In addition, we show here that a-syn caused synaptotoxic failure associated with a decrease in SV2, a membrane protein of synaptic vesicles associated with neurotransmitter release. In conclusion, extracellular a-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.
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Artículo de publicación ISI
Patrocinador
CONICYT
FEBS
Chilean Government
Anillo-PBCT ACT-04
FONDECYT
1100502
1140473
Spanish Ministerio de Economia y Competitividad
FIS PI10/00587
ISCIII-RETIC RED HERACLES RD06/0009/002-FEDER
La Marato de TV3
100310
Victorian Government
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J. Neurochem. (2015) 132, 731--741
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