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Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson's disease

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  • Luis Fonseca-Ornelas, Harvard University
  • ,
  • Thibault Viennet
  • Matteo Rovere, Harvard University
  • ,
  • Haiyang Jiang, Harvard University
  • ,
  • Lei Liu, Harvard University
  • ,
  • Silke Nuber, Harvard University
  • ,
  • Maria Ericsson, Harvard University
  • ,
  • Haribabu Arthanari, Dana-Farber Cancer Institute, Harvard University
  • ,
  • Dennis J. Selkoe, Harvard University

While misfolding of alpha-synuclein (αSyn) is central to the pathogenesis of Parkinson's disease (PD), fundamental questions about its structure and function at the synapse remain unanswered. We examine synaptosomes from non-transgenic and transgenic mice expressing wild-type human αSyn, the E46K fPD-causing mutation, or an amplified form of E46K (“3K”). Synaptosomes from mice expressing the 3K mutant show reduced Ca2+-dependent vesicle exocytosis, altered synaptic vesicle ultrastructure, decreased SNARE complexes, and abnormal levels of certain synaptic proteins. With our intra-synaptosomal nuclear magnetic resonance (NMR) method, we reveal that WT αSyn participates in heterogeneous interactions with synaptic components dependent on endogenous αSyn and synaptosomal integrity. The 3K mutation markedly alters these interactions. The synaptic microenvironment is necessary for αSyn to reach its native conformations and establish a physiological interaction network. Its inability to populate diverse conformational ensembles likely represents an early step in αSyn dysfunction that contributes to the synaptotoxicity observed in synucleinopathies.

Original languageEnglish
Article number109333
JournalCell Reports
Number of pages17
Publication statusPublished - 6 Jul 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

    Research areas

  • alpha-synuclein, in-cell NMR, neurodegeneration, Parkinson's disease, post-translational modifications, protein folding, synapse

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