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
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Acceso en línea:https://doaj.org/article/0c38ccc85024480b8c6ce7d146030f9f
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Sumario: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.