Schindler, F;
Praedel, N;
Neuendorf, N;
Kunz, S;
Schnoegl, S;
Mason, MA;
Taxy, BA;
... Wanker, EE; + view all
(2021)
Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington's Disease Knock-in Mice.
Frontiers in Neuroscience
, 15
, Article 682172. 10.3389/fnins.2021.682172.
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Abstract
The deposition of mutant huntingtin (mHTT) protein aggregates in neurons of patients is a pathological hallmark of Huntington’s disease (HD). Previous investigations in cell-free and cell-based disease models showed mHTT exon-1 (mHTTex1) fragments with pathogenic polyglutamine (polyQ) tracts (>40 glutamines) to self-assemble into highly stable, β-sheet-rich protein aggregates with a fibrillar morphology. HD knock-in mouse models have not been extensively studied with regard to mHTT aggregation. They endogenously produce full-length mHTT with a pathogenic polyQ tract as well as mHTTex1 fragments. Here, we demonstrate that seeding-competent, fibrillar mHTT aggregates can be readily detected in brains of zQ175 knock-in HD mice. To do this, we applied a highly sensitive FRET-based protein amplification assay that is capable of detecting seeding-competent mHTT aggregate species down to the femtomolar range. Furthermore, we show that fibrillar structures with an average length of ∼200 nm can be enriched with aggregate-specific mouse and human antibodies from zQ175 mouse brain extracts through immunoprecipitations, confirming that such structures are formed in vivo. Together these studies indicate that small, fibrillar, seeding-competent mHTT structures are prominent aggregate species in brains of zQ175 mice.
| Type: | Article |
|---|---|
| Title: | Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington's Disease Knock-in Mice |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fnins.2021.682172 |
| Publisher version: | http://dx.doi.org/10.3389/fnins.2021.682172 |
| Language: | English |
| Additional information: | Copyright © 2021 Schindler, Praedel, Neuendorf, Kunz, Schnoegl, Mason, Taxy, Bates, Khoshnan, Priller, Grimm, Maier, Boeddrich and Wanker. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | Huntington's disease, aggregates, seeding, mHTT, zQ175, brain, protein misfolding, FRASE assay, NEURONAL INTRANUCLEAR INCLUSIONS, MUTANT HUNTINGTIN, DYSTROPHIC NEURITES, MOUSE MODELS, PROTEIN, FRAGMENTS, EXON-1, QUANTIFICATION, NUCLEI, BODIES |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10131529 |
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