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SUMMARY:The role of DNAJB6 in protein Homeostasis - Harm H. Kampinga Depar
 tment of Cell Biology\, University Medical Center Groningen\, University o
 f Groningen\, The Netherlands
DTSTART:20180125T143000Z
DTEND:20180125T153000Z
UID:TALK97654@talks.cam.ac.uk
CONTACT:John Skidmore
DESCRIPTION:DNAJB6 is a member of the DNAJ family\, the largest family of 
 Hsp70 co-chaperones. Over the last 7 years\, we have accumulated strong ev
 idence that DNAJB6 is an extremely efficient suppressor of amyloid formati
 on\, initiated by polyglutamine proteins involved in Huntington’s diseas
 e). In vitro and in cell models\, canonical chaperones\, known to act on e
 xposed (polyQ-flanking) hydrophobic stretches\, were far less or not effec
 tive under the conditions we used. DNAJB6 and -8 were effective also on ot
 her polyQ proteins (polyQ ataxin-3\, polyQ-AR)\, suggesting that they act 
 on the polyQ core-driven aggregation. DNAJB6 co-expression with polyQ expr
 ession constructs also strongly reduced polyQ aggregation in vivo and dela
 yed related degenerative effects in tadpoles (huntington)\, fruitflies (hu
 ntington and ataxin-3)\, and mouse (huntington) models. Structure-function
  identify a specific S/T-rich stretch as the substrate-binding\, aggregati
 on-suppressing motif and reveal dynamic oligomerization as crucial for DNA
 JB6 function. DNAJB6 knockout cells\, generated by CRISPR\, are hypersensi
 tive to polyQ aggregation\, demonstrating that basal expression levels are
  important for cells as defense against amyloidogenesis. Next\, we generat
 ed 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 i
 n 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.
LOCATION:The Sackler Lecture Theatre (Level 7) Wellcome Trust/MRC Building
 \, CIMR\, Addenbrooke's Site
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