Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers

Abstract The primary hallmark of Parkinson's disease (PD) is the generation of Lewy bodies of which major component is α-synuclein (α-Syn). Because of increasing evidence of the fundamental roles of α-Syn oligomers in disease progression, α-Syn oligomers have become potential targets for therap...

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Autores principales:	Gyeongji Yoo, Sanghun Yeou, Jung Bae Son, Yeon-Kyun Shin, Nam Ki Lee
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5efb5ee1fb0649f6922c3aaf4066f69e
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spelling	oai:doaj.org-article:5efb5ee1fb0649f6922c3aaf4066f69e2021-12-02T15:00:19ZCooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers10.1038/s41598-021-90503-02045-2322https://doaj.org/article/5efb5ee1fb0649f6922c3aaf4066f69e2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90503-0https://doaj.org/toc/2045-2322Abstract The primary hallmark of Parkinson's disease (PD) is the generation of Lewy bodies of which major component is α-synuclein (α-Syn). Because of increasing evidence of the fundamental roles of α-Syn oligomers in disease progression, α-Syn oligomers have become potential targets for therapeutic interventions for PD. One of the potential toxicities of α-Syn oligomers is their inhibition of SNARE-mediated vesicle fusion by specifically interacting with vesicle-SNARE protein synaptobrevin-2 (Syb2), which hampers dopamine release. Here, we show that α-Syn monomers and oligomers cooperatively inhibit neuronal SNARE-mediated vesicle fusion. α-Syn monomers at submicromolar concentrations increase the fusion inhibition by α-Syn oligomers. This cooperative pathological effect stems from the synergically enhanced vesicle clustering. Based on this cooperative inhibition mechanism, we reverse the fusion inhibitory effect of α-Syn oligomers using small peptide fragments. The small peptide fragments, derivatives of α-Syn, block the binding of α-Syn oligomers to Syb2 and dramatically reverse the toxicity of α-Syn oligomers in vesicle fusion. Our findings demonstrate a new strategy for therapeutic intervention in PD and related diseases based on this specific interaction of α-Syn.Gyeongji YooSanghun YeouJung Bae SonYeon-Kyun ShinNam Ki LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gyeongji Yoo Sanghun Yeou Jung Bae Son Yeon-Kyun Shin Nam Ki Lee Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers
description	Abstract The primary hallmark of Parkinson's disease (PD) is the generation of Lewy bodies of which major component is α-synuclein (α-Syn). Because of increasing evidence of the fundamental roles of α-Syn oligomers in disease progression, α-Syn oligomers have become potential targets for therapeutic interventions for PD. One of the potential toxicities of α-Syn oligomers is their inhibition of SNARE-mediated vesicle fusion by specifically interacting with vesicle-SNARE protein synaptobrevin-2 (Syb2), which hampers dopamine release. Here, we show that α-Syn monomers and oligomers cooperatively inhibit neuronal SNARE-mediated vesicle fusion. α-Syn monomers at submicromolar concentrations increase the fusion inhibition by α-Syn oligomers. This cooperative pathological effect stems from the synergically enhanced vesicle clustering. Based on this cooperative inhibition mechanism, we reverse the fusion inhibitory effect of α-Syn oligomers using small peptide fragments. The small peptide fragments, derivatives of α-Syn, block the binding of α-Syn oligomers to Syb2 and dramatically reverse the toxicity of α-Syn oligomers in vesicle fusion. Our findings demonstrate a new strategy for therapeutic intervention in PD and related diseases based on this specific interaction of α-Syn.
format	article
author	Gyeongji Yoo Sanghun Yeou Jung Bae Son Yeon-Kyun Shin Nam Ki Lee
author_facet	Gyeongji Yoo Sanghun Yeou Jung Bae Son Yeon-Kyun Shin Nam Ki Lee
author_sort	Gyeongji Yoo
title	Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers
title_short	Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers
title_full	Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers
title_fullStr	Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers
title_full_unstemmed	Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers
title_sort	cooperative inhibition of snare-mediated vesicle fusion by α-synuclein monomers and oligomers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5efb5ee1fb0649f6922c3aaf4066f69e
work_keys_str_mv	AT gyeongjiyoo cooperativeinhibitionofsnaremediatedvesiclefusionbyasynucleinmonomersandoligomers AT sanghunyeou cooperativeinhibitionofsnaremediatedvesiclefusionbyasynucleinmonomersandoligomers AT jungbaeson cooperativeinhibitionofsnaremediatedvesiclefusionbyasynucleinmonomersandoligomers AT yeonkyunshin cooperativeinhibitionofsnaremediatedvesiclefusionbyasynucleinmonomersandoligomers AT namkilee cooperativeinhibitionofsnaremediatedvesiclefusionbyasynucleinmonomersandoligomers
_version_	1718389202773606400

Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers

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