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

dc.contributor.authorBusch, David J.
dc.contributor.authorOliphint, Paul A.
dc.contributor.authorWalsh, Rylie B.
dc.contributor.authorBanks, Susan M. L.
dc.contributor.authorWoods, Wendy S.
dc.contributor.authorGeorge, Julia M.
dc.contributor.authorMorgan, Jennifer R.
dc.date.accessioned2018-03-28T00:23:08Z
dc.date.available2018-03-28T00:23:08Z
dc.date.issued2014-10
dc.description.abstractParkinson'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.identifier.citationBusch, 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.issn1939-4586 (online)
dc.identifier.urihttps://www.molbiolcell.org/doi/10.1091/mbc.e14-02-0708
dc.identifier.urihttp://hdl.handle.net/11416/377
dc.language.isoen_USen_US
dc.publisherMolecular Biology of the Cell (MBoC)en_US
dc.subjectFish Proteins metabolismen_US
dc.subjectSynapses physiologyen_US
dc.subjectSynaptic Vesicles metabolismen_US
dc.subjectAmino Acid Sequenceen_US
dc.subjectMolecular Sequence Dataen_US
dc.titleAcute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulationen_US
dc.typeArticleen_US

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