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The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model

Kakkar, Vaishali; Månsson, Cecilia LU ; de Mattos, Eduardo P.; Bergink, Steven; van der Zwaag, Marianne; van Waarde, Maria A W H; Kloosterhuis, Niels J.; Melki, Ronald; van Cruchten, Remco T P and Al-Karadaghi, Salam LU , et al. (2016) In Molecular Cell 62(2). p.272-283
Abstract

Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads... (More)

Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases. Kakkar et al. show that DNAJB6 is a chaperone that inhibits early steps in the formation of polyQ amyloid fibrils. An S/T-rich region in DNAJB6 is crucial for this function. In a polyQ mouse model, the inhibitory effects of DNAJB6 delay disease onset and increase lifespan.

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Molecular Cell
volume
62
issue
2
pages
12 pages
publisher
Cell Press
external identifiers
  • scopus:84963566241
  • wos:000374643900012
ISSN
1097-2765
DOI
10.1016/j.molcel.2016.03.017
language
English
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yes
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3adfcbeb-dc8c-46df-9414-25c3c09c8db7
date added to LUP
2016-05-18 11:06:00
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2017-08-06 05:07:40
@article{3adfcbeb-dc8c-46df-9414-25c3c09c8db7,
  abstract     = {<p>Expanded CAG repeats lead to debilitating neurodegenerative disorders characterized by aggregation of proteins with expanded polyglutamine (polyQ) tracts. The mechanism of aggregation involves primary and secondary nucleation steps. We show how a noncanonical member of the DNAJ-chaperone family, DNAJB6, inhibits the conversion of soluble polyQ peptides into amyloid fibrils, in particular by suppressing primary nucleation. This inhibition is mediated by a serine/threonine-rich region that provides an array of surface-exposed hydroxyl groups that bind to polyQ peptides and may disrupt the formation of the H bonds essential for the stability of amyloid fibrils. Early prevention of polyQ aggregation by DNAJB6 occurs also in cells and leads to delayed neurite retraction even before aggregates are visible. In a mouse model, brain-specific coexpression of DNAJB6 delays polyQ aggregation, relieves symptoms, and prolongs lifespan, pointing to DNAJB6 as a potential target for disease therapy and tool for unraveling early events in the onset of polyQ diseases. Kakkar et al. show that DNAJB6 is a chaperone that inhibits early steps in the formation of polyQ amyloid fibrils. An S/T-rich region in DNAJB6 is crucial for this function. In a polyQ mouse model, the inhibitory effects of DNAJB6 delay disease onset and increase lifespan.</p>},
  author       = {Kakkar, Vaishali and Månsson, Cecilia and de Mattos, Eduardo P. and Bergink, Steven and van der Zwaag, Marianne and van Waarde, Maria A W H and Kloosterhuis, Niels J. and Melki, Ronald and van Cruchten, Remco T P and Al-Karadaghi, Salam and Arosio, Paolo and Dobson, Christopher M. and Knowles, Tuomas P J and Bates, Gillian P. and van Deursen, Jan M. and Linse, Sara and van de Sluis, Bart and Emanuelsson, Cecilia and Kampinga, Harm H.},
  issn         = {1097-2765},
  language     = {eng},
  month        = {04},
  number       = {2},
  pages        = {272--283},
  publisher    = {Cell Press},
  series       = {Molecular Cell},
  title        = {The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model},
  url          = {http://dx.doi.org/10.1016/j.molcel.2016.03.017},
  volume       = {62},
  year         = {2016},
}