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

TY - JOUR

T1 - Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson's disease

AU - Fonseca-Ornelas, Luis

AU - Viennet, Thibault

AU - Rovere, Matteo

AU - Jiang, Haiyang

AU - Liu, Lei

AU - Nuber, Silke

AU - Ericsson, Maria

AU - Arthanari, Haribabu

AU - Selkoe, Dennis J.

N1 - Publisher Copyright: © 2021 The Author(s)

PY - 2021/7/6

Y1 - 2021/7/6

N2 - 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.

AB - 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.

KW - alpha-synuclein

KW - in-cell NMR

KW - neurodegeneration

KW - Parkinson's disease

KW - post-translational modifications

KW - protein folding

KW - synapse

UR - http://www.scopus.com/inward/record.url?scp=85109000567&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.109333

DO - 10.1016/j.celrep.2021.109333

M3 - Journal article

C2 - 34233191

AN - SCOPUS:85109000567

SN - 2211-1247

VL - 36

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 109333

ER -