TY - JOUR
T1 - Hsc70 ameliorates the vesicle recycling defects caused by excess α-synuclein at synapses
AU - Banks, Susan M.L.
AU - Medeiros, Audrey T.
AU - McQuillan, Molly
AU - Busch, David J.
AU - Ibarraran-Viniegra, Ana Sofia
AU - Sousa, Rui
AU - Lafer, Eileen M.
AU - Morgan, Jennifer R.
N1 - Funding Information:
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.). *S.M.L.B. and A.T.M. contributed equally to this work.
Publisher Copyright:
© 2020 Banks et al.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Auxilin
KW - Chaperone
KW - Clathrin
KW - Clathrin-coated vesicles
KW - Endocytosis
KW - Lamprey
UR - http://www.scopus.com/inward/record.url?scp=85078868134&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078868134&partnerID=8YFLogxK
U2 - 10.1523/ENEURO.0448-19.2020
DO - 10.1523/ENEURO.0448-19.2020
M3 - Article
C2 - 31941659
AN - SCOPUS:85078868134
VL - 7
JO - eNeuro
JF - eNeuro
SN - 2373-2822
IS - 1
M1 - ENEURO.0448-19.2020
ER -