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Mol Cell. 2016 Apr 21;62(2):272-283. doi: 10.1016/j.molcel.2016.03.017. Epub 2016 Apr 14.

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

Author information

1
Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
2
Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
3
Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands; Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
4
Department of Pediatrics, Molecular Genetics Section, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
5
Neuroscience Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, 91190 Gif-Sur-Yvette, France.
6
Department of Chemistry, University of Cambridge, Cambridge CB2 1TN, UK.
7
Department of Medical and Molecular Genetics, King's College London, London WC2R 2LS, UK.
8
Mayo Clinic, Rochester, MN 55905, USA.
9
Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands. Electronic address: h.h.kampinga@umcg.nl.

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 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.

PMID:
27151442
DOI:
10.1016/j.molcel.2016.03.017
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