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Self-assembly of mutant huntingtin exon-1 fragments into large complex fibrillar structures involves nucleated branching

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Item Type:Article
Title:Self-assembly of mutant huntingtin exon-1 fragments into large complex fibrillar structures involves nucleated branching
Creators Name:Wagner, A.S. and Politi, A.Z. and Ast, A. and Bravo-Rodriguez, K. and Baum, K. and Buntru, A. and Strempel, N.U. and Brusendorf, L. and Hänig, C. and Boeddrich, A. and Plassmann, S. and Klockmeier, K. and Ramirez-Anguita, J.M. and Sanchez-Garcia, E. and Wolf, J. and Wanker, E.E.
Abstract:Huntingtin (HTT) fragments with extended polyglutamine (polyQ) 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 modelling 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.
Keywords:Huntingtin Fibrillogenesis, Aggregation Mechanism, Nucleation, Amyloidogenesis, Nucleated Fibril Branching
Source:Journal of Molecular Biology
ISSN:0022-2836
Publisher:Elsevier / Academic Press (U.S.A.)
Volume:430
Number:12
Page Range:1725-1744
Date:8 June 2018
Official Publication:https://doi.org/10.1016/j.jmb.2018.03.017
PubMed:View item in PubMed

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