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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2017
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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) |
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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 |
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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 |
work_keys_str_mv |
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