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Published June 22, 2021 | Published + Supplemental Material
Journal Article Open

Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington's Disease Knock-in Mice


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.

Additional Information

© 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. Received: 17 March 2021; Accepted: 31 May 2021; Published: 22 June 2021. We thank L. Delius for technical assistance and C. Hänig for support with editing of the manuscript. The research was funded by the CHDI Foundation, United States (to EW and GB), the UK Dementia Research Institute (UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK, to GB and JP), and the DFG SFB/TRR167-2 B07, Germany (to JP). Data Availability Statement: The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s. Ethics Statement: The animal study was reviewed and approved by University College London Ethical Review Process Committee. Author Contributions: FS, NP, NN, and AB planned and performed the immunoprecipitations, FRASE assays, TEM and biochemical analysis. SK performed TEM analysis. AK generated PHP1-4 antibodies. GB discussed the experiments and results. MM, JG, and JP provided and contributed to the generation and characterization of human antibodies Ab-A, -B, and -Ctrl antibodies. MAM, BT, and GB provided mouse tissues. FS, SS, AB, and EW co-ordinated the study and edited the manuscript. EW designed the study and wrote the manuscript, with contributions from JP, GB, MM, SS, and AB. All authors contributed to the article and approved the submitted version. Conflict of Interest: MM and JG are co-inventors on patent number WO2016016278A2 entitled "Human-derived anti-huntingtin (htt) antibodies and uses thereof." MM and JG are employees and shareholders of Neurimmune AG, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Published - fnins-15-682172.pdf

Supplemental Material - 5477205.zip


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August 20, 2023
October 23, 2023