The role of DNAJB6 in protein Homeostasis

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• Harm H. Kampinga Department of Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands
• Thursday 25 January 2018, 14:30-15:30
• The Sackler Lecture Theatre (Level 7) Wellcome Trust/MRC Building, CIMR, Addenbrooke's Site.

If you have a question about this talk, please contact John Skidmore.

DNAJB6 is a member of the DNAJ family, the largest family of Hsp70 co-chaperones. Over the last 7 years, we have accumulated strong evidence that DNAJB6 is an extremely efficient suppressor of amyloid formation, initiated by polyglutamine proteins involved in Huntington’s disease). In vitro and in cell models, canonical chaperones, known to act on exposed (polyQ-flanking) hydrophobic stretches, were far less or not effective under the conditions we used. DNAJB6 and -8 were effective also on other polyQ proteins (polyQ ataxin-3, polyQ-AR), suggesting that they act on the polyQ core-driven aggregation. DNAJB6 co-expression with polyQ expression constructs also strongly reduced polyQ aggregation in vivo and delayed related degenerative effects in tadpoles (huntington), fruitflies (huntington and ataxin-3), and mouse (huntington) models. Structure-function identify a specific S/T-rich stretch as the substrate-binding, aggregation-suppressing motif and reveal dynamic oligomerization as crucial for DNAJB6 function. DNAJB6 knockout cells, generated by CRISPR , are hypersensitive to polyQ aggregation, demonstrating that basal expression levels are important for cells as defense against amyloidogenesis. Next, we generated iPS cells from SCA3 patients. Neurons derived from these iPS cells show no spontaneous aggregate formation. However, upon glutamate-treatment, aggregates form in SCA3polyQ neurons but not in neural stem cells (NSCs). Analysis of chaperone protein expression reveals a drastic reorganization of the chaperone network during differentiation, including a substantial loss of expression DNAJB6 in neurons. Intriguingly, knockdown of DNAJB6 in NSCs derived from SCA3polyQ patients was found to result in spontaneous SCA3 polyQ aggregation. Together, these data suggest that DNAJB6 activity is a key factor in neuronal sensitivity to polyQ aggregation and toxicity and urges for insights in mechanisms that can potentiate its activity and searches for compounds that can do so.

This talk is part of the Cambridge Neuroscience Seminars series.

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