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

While misfolding of alpha-synuclein (alpha Syn) 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 alpha Syn, 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 alpha Syn participates in heterogeneous interactions with synaptic components dependent on endogenous alpha Syn and synaptosomal integrity. The 3K mutation markedly alters these interactions. The synaptic microenvironment is necessary for alpha Syn to reach its native conformations and establish a physiological interaction network. Its inability to populate diverse conformational ensembles likely represents an early step in alpha Syn dysfunction that contributes to the synaptotoxicity observed in synucleinopathies.