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

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Banks, S. M. L., Medeiros, A. T., McQuillan, M., Busch, D. J., Ibarraran-Viniegra, A. S., Sousa, R., Lafer, E. M., & Morgan, J. R. Hsc70 ameliorates the vesicle recycling defects caused by excess alpha-synuclein at synapses. Eneuro, 7(1), (2020): ENEURO.0448-19.2020, doi: 10.1523/ENEURO.0448-19.2020.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 γ-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.This work was supported by Department of Health and Human Services/National Institutes of Health (HHS/NIH) National Institute of Neurological Disorders and Stroke/National Institute on Aging Grant R01NS078165 (to J.R.M.) and HHS/NIH National Institute of General Medical Sciences Grant R01GM118933 (to E.M.L. and R.S.)