The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation

Abstract A major hallmark of Parkinson’s disease (PD) is the presence of Lewy bodies (LBs) in certain neuronal tissues. LBs are protein-rich inclusions, in which α-synuclein (α-syn) is the most abundant protein. Since these inclusions are not present in healthy individuals, despite the high concentr...

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Autores principales:	Francesco A. Aprile, Emma Källstig, Galina Limorenko, Michele Vendruscolo, David Ron, Christian Hansen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0c38ccc85024480b8c6ce7d146030f9f
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spelling	oai:doaj.org-article:0c38ccc85024480b8c6ce7d146030f9f2021-12-02T15:05:11ZThe molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation10.1038/s41598-017-08324-z2045-2322https://doaj.org/article/0c38ccc85024480b8c6ce7d146030f9f2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08324-zhttps://doaj.org/toc/2045-2322Abstract A major hallmark of Parkinson’s disease (PD) is the presence of Lewy bodies (LBs) in certain neuronal tissues. LBs are protein-rich inclusions, in which α-synuclein (α-syn) is the most abundant protein. Since these inclusions are not present in healthy individuals, despite the high concentration of α-syn in neurons, it is important to investigate whether natural control mechanisms are present to efficiently suppress α-syn aggregation. Here, we demonstrate that a CRISPR/Cas9-mediated knockout (KO) of a DnaJ protein, DNAJB6, in HEK293T cells expressing α-syn, causes a massive increase in α-syn aggregation. Upon DNAJB6 re-introduction into these DNAJB6-KO HEK293T-α-syn cells, aggregation is reduced to the level of the parental cells. We then show that the suppression of α-syn aggregation is dependent on the J-domain of DNAJB6, as the catalytically inactive protein, which carries the H31Q mutation, does not suppress aggregation, when re-introduced into DNAJB6-KO cells. We further demonstrate, that the suppression of α-syn aggregation is dependent on the molecular chaperone Hsp70, which is consistent with the well-known function of J-domains of transferring unfolded and misfolded proteins to Hsp70. These data identify a natural control strategy to suppress α-syn aggregation and suggest potential therapeutic approaches to prevent or treat PD and related disorders.Francesco A. AprileEmma KällstigGalina LimorenkoMichele VendruscoloDavid RonChristian HansenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Francesco A. Aprile Emma Källstig Galina Limorenko Michele Vendruscolo David Ron Christian Hansen The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation
description	Abstract A major hallmark of Parkinson’s disease (PD) is the presence of Lewy bodies (LBs) in certain neuronal tissues. LBs are protein-rich inclusions, in which α-synuclein (α-syn) is the most abundant protein. Since these inclusions are not present in healthy individuals, despite the high concentration of α-syn in neurons, it is important to investigate whether natural control mechanisms are present to efficiently suppress α-syn aggregation. Here, we demonstrate that a CRISPR/Cas9-mediated knockout (KO) of a DnaJ protein, DNAJB6, in HEK293T cells expressing α-syn, causes a massive increase in α-syn aggregation. Upon DNAJB6 re-introduction into these DNAJB6-KO HEK293T-α-syn cells, aggregation is reduced to the level of the parental cells. We then show that the suppression of α-syn aggregation is dependent on the J-domain of DNAJB6, as the catalytically inactive protein, which carries the H31Q mutation, does not suppress aggregation, when re-introduced into DNAJB6-KO cells. We further demonstrate, that the suppression of α-syn aggregation is dependent on the molecular chaperone Hsp70, which is consistent with the well-known function of J-domains of transferring unfolded and misfolded proteins to Hsp70. These data identify a natural control strategy to suppress α-syn aggregation and suggest potential therapeutic approaches to prevent or treat PD and related disorders.
format	article
author	Francesco A. Aprile Emma Källstig Galina Limorenko Michele Vendruscolo David Ron Christian Hansen
author_facet	Francesco A. Aprile Emma Källstig Galina Limorenko Michele Vendruscolo David Ron Christian Hansen
author_sort	Francesco A. Aprile
title	The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation
title_short	The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation
title_full	The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation
title_fullStr	The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation
title_full_unstemmed	The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation
title_sort	molecular chaperones dnajb6 and hsp70 cooperate to suppress α-synuclein aggregation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0c38ccc85024480b8c6ce7d146030f9f
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The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation

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