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

Lin, HK and Boatz, JC and Krabbendam, IE and Kodali, R and Hou, Z and Wetzel, R and Dolga, AM and Poirier, MA and Van Der Wel, PCA (2017) Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core. Nature Communications, 8.

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Abstract

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 α-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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lin, HK
Boatz, JC
Krabbendam, IE
Kodali, R
Hou, Z
Wetzel, R
Dolga, AM
Poirier, MA
Van Der Wel, PCApvdwel@pitt.eduPVDWEL0000-0002-5390-3321
Date: 24 May 2017
Date Type: Publication
Journal or Publication Title: Nature Communications
Volume: 8
DOI or Unique Handle: 10.1038/ncomms15462
Schools and Programs: School of Medicine > Structural Biology
Refereed: Yes
Date Deposited: 28 Sep 2017 20:19
Last Modified: 13 Oct 2017 21:58
URI: http://d-scholarship.pitt.edu/id/eprint/33218

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