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Acute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation

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dc.contributor.author Busch, David J.
dc.contributor.author Oliphint, Paul A.
dc.contributor.author Walsh, Rylie B.
dc.contributor.author Banks, Susan M. L.
dc.contributor.author Woods, Wendy S.
dc.contributor.author George, Julia M.
dc.contributor.author Morgan, Jennifer R.
dc.date.accessioned 2018-03-28T00:23:08Z
dc.date.available 2018-03-28T00:23:08Z
dc.date.issued 2014-10
dc.identifier.citation Busch, D. J., Oliphint, P. A., Walsh, R. B., Banks, S. L., Woods, W. S., George, J. M., & Morgan, J. R. (2014). Acute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation. Molecular Biology Of The Cell, 25(24), 3926. en_US
dc.identifier.issn 1939-4586 (online)
dc.identifier.uri https://www.molbiolcell.org/doi/10.1091/mbc.e14-02-0708
dc.identifier.uri http://hdl.handle.net/11416/377
dc.description.abstract Parkinson's disease is associated with multiplication of the α-synuclein gene and abnormal accumulation of the protein. In animal models, α-synuclein overexpression broadly impairs synaptic vesicle trafficking. However, the exact steps of the vesicle trafficking pathway affected by excess α-synuclein and the underlying molecular mechanisms remain unknown. Therefore we acutely increased synuclein levels at a vertebrate synapse and performed a detailed ultrastructural analysis of the effects on presynaptic membranes. At stimulated synapses (20 Hz), excess synuclein caused a loss of synaptic vesicles and an expansion of the plasma membrane, indicating an impairment of vesicle recycling. The N-terminal domain (NTD) of synuclein, which folds into an α-helix, was sufficient to reproduce these effects. In contrast, α-synuclein mutants with a disrupted N-terminal α-helix (T6K and A30P) had little effect under identical conditions. Further supporting this model, another α-synuclein mutant (A53T) with a properly folded NTD phenocopied the synaptic vesicle recycling defects observed with wild type. Interestingly, the vesicle recycling defects were not observed when the stimulation frequency was reduced (5 Hz). Thus excess α-synuclein impairs synaptic vesicle recycling evoked during intense stimulation via a mechanism that requires a properly folded N-terminal α-helix. en_US
dc.language.iso en_US en_US
dc.publisher Molecular Biology of the Cell (MBoC) en_US
dc.subject Fish Proteins metabolism en_US
dc.subject Synapses physiology en_US
dc.subject Synaptic Vesicles metabolism en_US
dc.subject Amino Acid Sequence en_US
dc.subject Molecular Sequence Data en_US
dc.title Acute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation en_US
dc.type Article en_US

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