AUTHOR=Román-Vendrell Cristina , Medeiros Audrey T. , Sanderson John B. , Jiang Haiyang , Bartels Tim , Morgan Jennifer R. 

TITLE=Effects of Excess Brain-Derived Human α-Synuclein on Synaptic Vesicle Trafficking

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 15 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.639414

DOI=10.3389/fnins.2021.639414

ISSN=1662-453X

ABSTRACT=a-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases including Parkinson’s disease, dementia with Lewy bodies, and multiple systems atrophy, a-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of a-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of a-synuclein affect synapses where a-synuclein is normally expressed.  Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric a-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here we expand this knowledge by investigating the effects of native, physiological a-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically-folded multimeric a-synuclein with a minor component of monomeric a-synuclein. After acute introduction of excess brain-derived human a-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called “cisternae”. In addition, brain-derived a-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone.  In contrast to monomeric or dimeric a-synuclein, the brain-derived multimeric a-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of a-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.