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

Vaishali Kakkar, Cecilia Mansson, Eduardo P. de Mattos, Steven Bergink, Marianne van der Zwaag, M A W H van Waarde-Verhagen, Niels J. Kloosterhuis, Ronald Melki, Remco T. P. van Cruchten, Salam Al-Karadaghi, Paolo Arosio, Christopher M. Dobson, Tuomas P. J. Knowles, Gillian P. Bates, Jan M. van Deursen, Sara Linse, Bart van de Sluis, Cecilia Emanuelsson, Harm H. Kampinga*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

108 Citaten (Scopus)


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.

Originele taal-2English
Pagina's (van-tot)272-283
Aantal pagina's12
TijdschriftMolecular Cell
Nummer van het tijdschrift2
StatusPublished - 21-apr.-2016

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