Artículo de revista
Extracellular alpha-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane
Fecha
2015Registro en:
J. Neurochem. (2015) 132, 731--741
14714159
00223042
10.1111/jnc.13060
Autor
Pacheco, Carla R.
Morales, Camila N.
Ramírez, Alejandra E.
Muñoz, Francisco J.
Gallegos, Scarlet S.
Caviedes, Pablo A.
Aguayo, Luis G.
Opazo, Carlos M.
Institución
Resumen
It has been postulated that the accumulation of extracellular asynuclein (a-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.