Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson’s disease
Luis Fonseca‐Ornelas, Thibault Viennet, Matteo Rovere, Haiyang Jiang, Lei Liu, Silke Nuber, Maria Ericsson, Haribabu Arthanari, Dennis J. Selkoe
Abstract
-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.