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

作者：Busch David J; Oliphint Paul A; Walsh Rylie B; Banks Susan M L; Woods Wendy S; George Julia M; Morgan Jennifer R^*

来源：Molecular Biology of the Cell, 2014, 25(24): 3926-3941.

DOI：10.1091/mbc.E14-02-0708

Parkinson%26apos;s disease is associated with multiplication of the alpha-synuclein gene and abnormal accumulation of the protein. In animal models, alpha-synuclein overexpression broadly impairs synaptic vesicle trafficking. However, the exact steps of the vesicle trafficking pathway affected by excess alpha-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 alpha-helix, was sufficient to reproduce these effects. In contrast, alpha-synuclein mutants with a disrupted N-terminal alpha-helix (T6K and A30P) had little effect under identical conditions. Further supporting this model, another alpha-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 alpha-synuclein impairs synaptic vesicle recycling evoked during intense stimulation via a mechanism that requires a properly folded N-terminal alpha-helix.

• 出版日期2014-12-1