Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts

EBioMedicine

Michela Matteoli¹  Elisabetta Menna¹  Serena Camerini²  Marco Crescenzi²  Silvia Ferrara³  Flavia Antonucci³  Tiziano Catelani⁴  Roberto Marotta⁴  Silvia Seghezza⁵  Claudio Canale⁵  Marco Emanuele⁶  Evelina Chieregatti⁶  Alessandro Esposito⁶ 

[1] CNR Institute of Neuroscience, Milan, Italy;Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita, Rome, Italy;Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy;Department of Nanochemistry, Istituto Italiano di Tecnologia, Genoa, Italy;Department of Nanophysics, Istituto Italiano di Tecnologia, Genoa, Italy;Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy;

关键词: Alpha-synuclein;    Lipid rafts;    Post-synaptic density;    Long term potentiation;    Synaptic vesicles' mobilization;    Casein kinase 2;   

DOI  :  10.1016/j.ebiom.2016.03.038

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown