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

alpha-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 system atrophy, alpha-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 alpha-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 alpha-synuclein affect synapses where alpha-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric alpha-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 alpha-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric alpha-synuclein with a minor component of monomeric alpha-synuclein. After acute introduction of excess brain-derived human alpha-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 alpha-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric alpha-synuclein, the brain-derived multimeric alpha-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human alpha-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of alpha-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess alpha-synuclein contributes to synaptic deficits and disease phenotypes.

Automated summary

Alpha-synuclein accumulates in neurodegenerative diseases, affecting synaptic function and leading to motor, cognitive, and autonomic dysfunction. Different molecular species of alpha-synuclein result in distinct trafficking defects at synapses, with multimeric alpha-synuclein causing intracellular vesicle trafficking impairment.