Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts.
Alpha-synuclein (αSyn) interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR) and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
Marco
M
Emanuele
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
Alessandro
A
Esposito
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita, Rome, Italy.
Serena
S
Camerini
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Flavia
F
Antonucci
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Silvia
S
Ferrara
Department of Nanophysics, Istituto Italiano di Tecnologia, Genoa, Italy.
Silvia
S
Seghezza
Department of Nanochemistry, Istituto Italiano di Tecnologia, Genoa, Italy.
Tiziano
T
Catelani
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita, Rome, Italy.
Marco
M
Crescenzi
Department of Nanochemistry, Istituto Italiano di Tecnologia, Genoa, Italy.
Roberto
R
Marotta
Department of Nanophysics, Istituto Italiano di Tecnologia, Genoa, Italy.
Claudio
C
Canale
CNR Institute of Neuroscience, Milan, Italy; Humanitas Research Hospital, Rozzano, Italy.
Michela
M
Matteoli
CNR Institute of Neuroscience, Milan, Italy; Humanitas Research Hospital, Rozzano, Italy.
Elisabetta
E
Menna
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy. Electronic address: evelina.chieregatti@iit.it.
Evelina
E
Chieregatti
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D051844:alpha-Synuclein / Q000494:pharmacology*
D016194:Receptors, N-Methyl-D-Aspartate; D051844:alpha-Synuclein; D002118:Calcium
Alpha-synuclein; Casein kinase 2; Lipid rafts; Long term potentiation; Post-synaptic density; Synaptic vesicles' mobilization