Hsc70 Ameliorates the Vesicle Recycling Defects Caused by Excess α-Synuclein at Synapses
| Autor: | Susan M. L. Banks, Rui J Sousa, Eileen M. Lafer, Subhojit Roy, Jennifer R. Morgan, Molly McQuillan, Ana Sofia Ibarraran-Viniegra, David J. Busch, Audrey T. Medeiros |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
biology Chemistry Lamprey Vesicle biology.organism_classification Synaptic vesicle Clathrin nervous system diseases Cell biology Synapse 03 medical and health sciences 0302 clinical medicine nervous system Chaperone (protein) mental disorders biology.protein Synuclein Synaptic vesicle recycling 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/517524 |
| Popis: | 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 synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to 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 to lamprey axons, Hsc70 availability was reduced at the 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 together 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 toxic impacts of excess α-synuclein at synapses, which may be of value for ameliorating synaptic defects in PD and other synuclein-linked diseases.SIGNIFICANCE STATEMENTSynaptic defects caused by α-synuclein overexpression are linked to cognitive deficits in PD and other diseases. However, the mechanisms by which excess α-synuclein impairs synaptic vesicle trafficking are unknown. Data presented here demonstrate that acute introduction of excess α-synuclein at a classical vertebrate synapse selectively inhibits CCV uncoating, leading to impaired vesicle recycling. Furthermore, increasing α-synuclein reduced synaptic levels of Hsc70, the clathrin uncoating ATPase. Subsequently increasing Hsc70 restored CCV uncoating and improved vesicle recycling. This study identifies a novel molecular mechanism underlying the α-synuclein-induced synaptic defects and presents one viable strategy for reversing them. |
| Databáze: | OpenAIRE |
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