Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core

Hsiang-Kai Lin, Jennifer C Boatz, Inge E. Krabbendam, Ravindra Kodali, Zhipeng Hou, Ronald Wetzel, Amalia M. Dolga, Michelle A Poirier, Patrick C A van der Wel

OnderzoeksoutputAcademicpeer review

64 Citaten (Scopus)
424 Downloads (Pure)

Samenvatting

Polyglutamine expansion in the huntingtin protein is the primary genetic cause of Huntington's disease (HD). Fragments coinciding with mutant huntingtin exon1 aggregate in vivo and induce HD-like pathology in mouse models. The resulting aggregates can have different structures that affect their biochemical behaviour and cytotoxic activity. Here we report our studies of the structure and functional characteristics of multiple mutant htt exon1 fibrils by complementary techniques, including infrared and solid-state NMR spectroscopies. Magic-angle-spinning NMR reveals that fibrillar exon1 has a partly mobile alpha-helix in its aggregation-accelerating N terminus, and semi-rigid polyproline II helices in the proline-rich flanking domain (PRD). The polyglutamine-proximal portions of these domains are immobilized and clustered, limiting access to aggregation-modulating antibodies. The polymorphic fibrils differ in their flanking domains rather than the polyglutamine amyloid structure. They are effective at seeding polyglutamine aggregation and exhibit cytotoxic effects when applied to neuronal cells.

Originele taal-2English
Artikelnummer15462
Aantal pagina's12
TijdschriftNature Communications
Volume8
DOI's
StatusPublished - 24-mei-2017

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