期刊
JOURNAL OF NEUROCHEMISTRY
卷 132, 期 6, 页码 731-741出版社
WILEY-BLACKWELL
DOI: 10.1111/jnc.13060
关键词
calcium; Parkinson's disease; perforation; porelike structures; alpha-synuclein
资金
- 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
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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