The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation
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Aprile, F., Källstig, E., Limorenko, G., Vendruscolo, M., Ron, D., & hansen, C. (2017). The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α-synuclein aggregation. Scientific Reports, 7 (9039)https://doi.org/10.1038/s41598-017-08324-z
A major hallmark of Parkinson’s disease (PD) is the presence Lewy bodies (LBs) in neuronal tissues. These are protein-rich inclusions primarily composed by the protein α-synuclein (α-syn), that are not present in healthy individuals, despite the high concentration of α-syn in neurons. This suggests the presence of natural control mechanisms that efficiently suppress α-syn aggregation. Here, we demonstrate that that CRISPR/Cas9 mediated knock out (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 was 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 that carries the H31Q mutation, did 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 could suggest new therapeutic approaches to prevent or treat PD and related disorders.
This study was supported by an INCA grant co-funded by the Marie Skłodowska Curie Actions FP7 and The Swedish Research Council, as well as it was funded by the Swedish Parkinsons foundation and Crafoordska Stiftelsen (C.H.). In addition, it was supported by grants from the Wellcome Trust (Wellcome 200848/Z/16/Z and a strategic award Wellcome 100140). D.R. is a Wellcome Trust Principal Research Fellow.FAA is supported by a Senior Research Fellowship award from the Alzheimer’s Society, UK (Grant Number 317, AS-SF-16-003).
WELLCOME TRUST (200848/Z/16/Z)
Alzheimer's Society (317 (AS-SF-16-003))
Wellcome Trust (100140/Z/12/Z)
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External DOI: https://doi.org/10.1038/s41598-017-08324-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267423
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