Publication Date:
2022-10-27
Description:
© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Roman-Vendrell, C., Medeiros, A. T., Sanderson, J. B., Jiang, H., Bartels, T., & Morgan, J. R. Effects of excess brain-derived human alpha-synuclein on synaptic vesicle trafficking. Frontiers in Neuroscience, 15, (2021): 639414, https://doi.org/10.3389./fnins.2021.639414
Description:
α-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, α-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 α-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 α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-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 α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-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 α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-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 α-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.
Description:
This work was supported by the NIH (NINDS/NIA R01NS078165 and R01NS078165-S1 to JM; NINDS U54-NS110435, R01-NS109209, and R21-NS107950 to TB); research funds from the Marine Biological Laboratory (to JM); grants from the UK Dementia Research Institute (DRI), which receives its funding from DRI Ltd., the UK Medical Research Council and Alzheimer’s Society, and Alzheimer’s Research UK (to TB); the Michael J. Fox Foundation (Ken Griffin Imaging Award to TB); a Parkinson’s Disease Foundation Stanley Fahn Award (PF-JFA-1884 to TB); the Eisai Pharmaceutical postdoctoral program to TB; and the Chan Zuckerberg Collaborative Pairs Initiative (to TB).
Keywords:
Clathrin mediated endocytosis
;
Electron microscopy
;
Endosome
;
Lamprey
;
Reticulospinal synapse
Repository Name:
Woods Hole Open Access Server
Type:
Article
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