Hsc70 ameliorates the vesicle recycling defects caused by excess α-synuclein at synapses

α-Synuclein overexpression and aggregation are linked to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal (RS) synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to an increase in endocytic intermediates and a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey +-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein, Hsc70 availability was reduced at stimulated synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 along with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the synaptic vesicle trafficking defects associated with excess α-synuclein, which may be of value for improving synaptic function in PD and other synuclein-linked diseases.

Keywords

Parkinson's disease, Dementia, Neurobehavioral disorders, Alpha-synuclein, Molecular chaperones, Synaptic vesicles

Citation

Banks, S. M. L., Medeiros, A. T., McQuillan, M., Busch, D. J., Ibarraran-Viniegra, A. S., Sousa, R., Lafer, E. M., & Morgan, J. R. (2020). Hsc70 ameliorates the vesicle recycling defects caused by excess α-synuclein at synapses. eNeuro, 7(1), ENEURO.0448-19.2020. https://doi.org/10.1523/ENEURO.0448-19.2020