Molecular Cell
Volume 62, Issue 2, 21 April 2016, Pages 272-283
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Article
The S/T-Rich Motif in the DNAJB6 Chaperone Delays Polyglutamine Aggregation and the Onset of Disease in a Mouse Model

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Highlights

  • The chaperone DNAJB6 inhibits polyQ aggregation at substoichiometric ratios

  • DNAJB6 inhibits nucleation and the subsequent formation of amyloid fibrils

  • DNAJB6 functionality depends on hydroxyl groups in a unique S/T-rich motif

  • DNAJB6 reduces aggregation, delays symptoms, and prolongs lifespan in polyQ mice

Summary

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.

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