CSPα reduces aggregates and rescues striatal dopamine release in α-synuclein transgenic mice
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain..
α-Synuclein aggregation at the synapse is an early event in Parkinson's disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and α-synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like α-synuclein, chaperones the SNARE complex assembly and controls neurotransmitter release. α-Synuclein can rescue neurodegeneration in CSPαKO mice. However, whether α-synuclein aggregation alters CSPα expression and function is unknown. Here we show that α-synuclein aggregation at the synapse is associated with a decrease in synaptic CSPα and a reduction in the complexes that CSPα forms with HSC70 and STGa. We further show that viral delivery of CSPα rescues in vitro the impaired vesicle recycling in PC12 cells with α-synuclein aggregates and in vivo reduces synaptic α-synuclein aggregates increasing monomeric α-synuclein and restoring normal dopamine release in 1-120hαSyn mice. These novel findings reveal a mechanism by which α-synuclein aggregation alters CSPα at the synapse, and show that CSPα rescues α-synuclein aggregation-related phenotype in 1-120hαSyn mice similar to the effect of α-synuclein in CSPαKO mice. These results implicate CSPα as a potential therapeutic target for the treatment of early-stage Parkinson's disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:144 |
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| Enthalten in: |
Brain : a journal of neurology - 144(2021), 6 vom: 28. Juli, Seite 1661-1669 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Caló, Laura [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.09.2021 Date Revised 01.02.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/brain/awab076 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM323161928 |
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| 100 | 1 | |a Caló, Laura |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CSPα reduces aggregates and rescues striatal dopamine release in α-synuclein transgenic mice |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 24.09.2021 | ||
| 500 | |a Date Revised 01.02.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. | ||
| 520 | |a α-Synuclein aggregation at the synapse is an early event in Parkinson's disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and α-synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like α-synuclein, chaperones the SNARE complex assembly and controls neurotransmitter release. α-Synuclein can rescue neurodegeneration in CSPαKO mice. However, whether α-synuclein aggregation alters CSPα expression and function is unknown. Here we show that α-synuclein aggregation at the synapse is associated with a decrease in synaptic CSPα and a reduction in the complexes that CSPα forms with HSC70 and STGa. We further show that viral delivery of CSPα rescues in vitro the impaired vesicle recycling in PC12 cells with α-synuclein aggregates and in vivo reduces synaptic α-synuclein aggregates increasing monomeric α-synuclein and restoring normal dopamine release in 1-120hαSyn mice. These novel findings reveal a mechanism by which α-synuclein aggregation alters CSPα at the synapse, and show that CSPα rescues α-synuclein aggregation-related phenotype in 1-120hαSyn mice similar to the effect of α-synuclein in CSPαKO mice. These results implicate CSPα as a potential therapeutic target for the treatment of early-stage Parkinson's disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CSPα | |
| 650 | 4 | |a DNAJ chaperone family | |
| 650 | 4 | |a Parkinson’s disease | |
| 650 | 4 | |a synapse | |
| 650 | 4 | |a α-synuclein | |
| 650 | 7 | |a HSP40 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a alpha-Synuclein |2 NLM | |
| 650 | 7 | |a cysteine string protein |2 NLM | |
| 650 | 7 | |a Dopamine |2 NLM | |
| 650 | 7 | |a VTD58H1Z2X |2 NLM | |
| 700 | 1 | |a Hidari, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Wegrzynowicz, Michal |e verfasserin |4 aut | |
| 700 | 1 | |a Dalley, Jeffrey W |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Bernard L |e verfasserin |4 aut | |
| 700 | 1 | |a Podgajna, Martyna |e verfasserin |4 aut | |
| 700 | 1 | |a Anichtchik, Oleg |e verfasserin |4 aut | |
| 700 | 1 | |a Carlson, Emma |e verfasserin |4 aut | |
| 700 | 1 | |a Klenerman, David |e verfasserin |4 aut | |
| 700 | 1 | |a Spillantini, Maria Grazia |e verfasserin |4 aut | |
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