title: The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model.
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.
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Kakkar
authors.affiliation: Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Månsson
authors.affiliation: 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.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: de Mattos
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Steven
authors.initials: S
authors.lastname: Bergink
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: van der Zwaag
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Maria A W H
authors.initials: MAWH
authors.lastname: van Waarde
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Niels J
authors.initials: NJ
authors.lastname: Kloosterhuis
authors.affiliation: Neuroscience Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, 91190 Gif-Sur-Yvette, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.affiliation: Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
authors.forename: Remco T P
authors.initials: RTP
authors.lastname: van Cruchten
authors.affiliation: Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
authors.forename: Salam
authors.initials: S
authors.lastname: Al-Karadaghi
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1TN, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1TN, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1TN, UK.
authors.forename: Tuomas P J
authors.initials: TPJ
authors.lastname: Knowles
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London WC2R 2LS, UK.
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.affiliation: Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.affiliation: Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Linse
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.affiliation: Department of Biochemistry and Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Emanuelsson
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands. Electronic address: h.h.kampinga@umcg.nl.
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga