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Fibril branching dominates self-assembly of mutant huntingtin exon-1 aggregates in vitro

Anne S. Wagner, Antonio Z. Politi, Anne Steinhof, Kenny Bravo-Rodriguez, Alexander Buntru, Nadine U. Strempel, Lydia Brusendorf, Christian Hänig, Annett Boeddrich, Stephanie Plassmann, Juan M. Ramirez-Anguita, Katharina Baum, Elsa Sanchez-Garcia, Jana Wolf, Erich E. Wanker
doi: https://doi.org/10.1101/195297
Anne S. Wagner
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Antonio Z. Politi
2Mathematical Modelling of Cellular Processes, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
3Present address: European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany
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Anne Steinhof
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Kenny Bravo-Rodriguez
4Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 2, 45470 Mülheim an der Ruhr, Germany
5Computational Chemistry and Biology, University Duisburg-Essen, Universitätsstr. 5, 45141 Essen, Germany
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Alexander Buntru
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Nadine U. Strempel
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Lydia Brusendorf
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Christian Hänig
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Annett Boeddrich
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Stephanie Plassmann
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Juan M. Ramirez-Anguita
4Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 2, 45470 Mülheim an der Ruhr, Germany
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Katharina Baum
2Mathematical Modelling of Cellular Processes, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Elsa Sanchez-Garcia
4Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 2, 45470 Mülheim an der Ruhr, Germany
5Computational Chemistry and Biology, University Duisburg-Essen, Universitätsstr. 5, 45141 Essen, Germany
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Jana Wolf
2Mathematical Modelling of Cellular Processes, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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  • For correspondence: ewanker@mdc-berlin.de jana.wolf@mdc-berlin.de
Erich E. Wanker
1Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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  • For correspondence: ewanker@mdc-berlin.de jana.wolf@mdc-berlin.de
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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 selfassembly of an aggregation-prone N-terminal HTT exon-1 fragment with 49 glutamines (Ex1Q49). We demonstrate 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 monomers, and (2) a fast secondary fibril-dependent nucleation process, which involves 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 primary nucleation and delays Ex1Q49 fibril assembly, comprehensive mathematical and computational modelling studies, and seeding experiments with small, preformed fibrillar Ex1Q49 aggregates. All results indicate that in vitro, HTT exon-1 fibrillar aggregates are formed by a branching mechanism.

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Posted October 19, 2017.
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Fibril branching dominates self-assembly of mutant huntingtin exon-1 aggregates in vitro
Anne S. Wagner, Antonio Z. Politi, Anne Steinhof, Kenny Bravo-Rodriguez, Alexander Buntru, Nadine U. Strempel, Lydia Brusendorf, Christian Hänig, Annett Boeddrich, Stephanie Plassmann, Juan M. Ramirez-Anguita, Katharina Baum, Elsa Sanchez-Garcia, Jana Wolf, Erich E. Wanker
bioRxiv 195297; doi: https://doi.org/10.1101/195297
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Fibril branching dominates self-assembly of mutant huntingtin exon-1 aggregates in vitro
Anne S. Wagner, Antonio Z. Politi, Anne Steinhof, Kenny Bravo-Rodriguez, Alexander Buntru, Nadine U. Strempel, Lydia Brusendorf, Christian Hänig, Annett Boeddrich, Stephanie Plassmann, Juan M. Ramirez-Anguita, Katharina Baum, Elsa Sanchez-Garcia, Jana Wolf, Erich E. Wanker
bioRxiv 195297; doi: https://doi.org/10.1101/195297

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