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

Marco Emanuele, Alessandro Esposito, Serena Camerini, Flavia Antonucci, Silvia Ferrara, Silvia Seghezza, Tiziano Catelani, Marco Crescenzi, Roberto Marotta, Claudio Canale, Michela Matteoli, Elisabetta Menna, Evelina Chieregatti

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalEBioMedicine
DOIs
Publication statusAccepted/In press - Nov 12 2015

Keywords

  • Alpha-synuclein
  • Casein kinase 2
  • Lipid rafts
  • Long term potentiation
  • Post-synaptic density
  • Synaptic vesicles' mobilization

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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  • Cite this

    Emanuele, M., Esposito, A., Camerini, S., Antonucci, F., Ferrara, S., Seghezza, S., Catelani, T., Crescenzi, M., Marotta, R., Canale, C., Matteoli, M., Menna, E., & Chieregatti, E. (Accepted/In press). Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts. EBioMedicine. https://doi.org/10.1016/j.ebiom.2016.03.038