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  Self-assembly of Mutant Huntingtin Exon-1 Fragments into Large Complex Fibrillar Structures Involves Nucleated Branching

Wagner, A. S., Politi, A. Z., Bravo-Rodriguez, K., Baum, K., Buntru, A., Strempel, N. U., et al. (2018). Self-assembly of Mutant Huntingtin Exon-1 Fragments into Large Complex Fibrillar Structures Involves Nucleated Branching. Journal of Molecular Biology (London), 430(12), 1725-1744. doi:10.1016/j.jmb.2018.03.017.

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 Creators:
Wagner, Anne S.1, Author
Politi, Antonio Z.2, Author
Bravo-Rodriguez, Kenny3, 4, Author              
Baum, Katharina2, Author
Buntru, Alexander1, Author
Strempel, Nadine U.1, Author
Brusendorf, Lydia1, Author
Hänig, Christian1, Author
Boeddrich, Annett1, Author
Plassmann, Stephanie1, Author
Klockmeier, Konrad1, Author
Ramirez-Anguita, Juan Manuel3, Author              
Sanchez-Garcia, Elsa3, 4, Author              
Wolf, Jana2, Author
Wanker, Erich E.1, Author
Affiliations:
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany, ou_persistent22              
2Mathematical Modelling of Cellular Processes, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany, ou_persistent22              
3Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1950289              
4Computational Biochemistry, University Duisburg-Essen, Universitätsstr. 2, 45141 Essen, Germany, ou_persistent22              

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Free keywords: Huntington fibrillogenesis; aggregation mechanism; nucleation; amyloidgenesis; nucleated fibril branching
 Abstract: Huntingtin (HTT) fragments with extended polyglutamine tracts self-assemble into amyloid-like fibrillar aggregates. Elucidating the fibril formation mechanism is critical for understanding Huntington's disease pathology and for developing novel therapeutic strategies. Here, we performed systematic experimental and theoretical studies to examine the self-assembly of an aggregation-prone N-terminal HTT exon-1 fragment with 49 glutamines (Ex1Q49). Using high-resolution imaging techniques such as electron microscopy and atomic force microscopy, we show that Ex1Q49 fragments in cell-free assays spontaneously convert into large, highly complex bundles of amyloid fibrils with multiple ends and fibril branching points. Furthermore, we present experimental evidence that two nucleation mechanisms control spontaneous Ex1Q49 fibrillogenesis: (1) a relatively slow primary fibril-independent nucleation process, which involves the spontaneous formation of aggregation-competent fibrillary structures, and (2) a fast secondary fibril-dependent nucleation process, which involves nucleated branching and promotes the rapid assembly of highly complex fibril bundles with multiple ends. The proposed aggregation mechanism is supported by studies with the small molecule O4, which perturbs early events in the aggregation cascade and delays Ex1Q49 fibril assembly, comprehensive mathematical and computational modeling studies, and seeding experiments with small, preformed fibrillar Ex1Q49 aggregates that promote the assembly of amyloid fibrils. Together, our results suggest that nucleated branching in vitro plays a critical role in the formation of complex fibrillar HTT exon-1 aggregates with multiple ends.

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Language(s): eng - English
 Dates: 2017-09-282018-03-192018-03-282018-06-08
 Publication Status: Published in print
 Pages: 20
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.jmb.2018.03.017
 Degree: -

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Title: Journal of Molecular Biology (London)
  Other : J Mol Biol
Source Genre: Journal
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Publ. Info: London : Academic Press
Pages: - Volume / Issue: 430 (12) Sequence Number: - Start / End Page: 1725 - 1744 Identifier: ISSN: 0022-2836
CoNE: https://pure.mpg.de/cone/journals/resource/954922646042