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| Item Type: | Article |
|---|---|
| Title: | Small, seeding-competent huntingtin fibrils are prominent aggregate species in brains of zQ175 Huntington's disease knock-in mice |
| Creators Name: | Schindler, F. and Praedel, N. and Neuendorf, N. and Kunz, S. and Schnoegl, S. and Mason, M.A. and Taxy, B.A. and Bates, G.P. and Khoshnan, A. and Priller, J. and Grimm, J. and Maier, M. and Boeddrich, A. and Wanker, E.E. |
| 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. |
| Keywords: | Huntington's Disease, Aggregates, Seeding, mHTT, zQ175, Brain, Protein Misfolding, FRASE Assay, Animals, Mice |
| Source: | Frontiers in Neuroscience |
| ISSN: | 1662-453X |
| Publisher: | Frontiers Media SA |
| Volume: | 15 |
| Page Range: | 682172 |
| Date: | 22 June 2021 |
| Official Publication: | https://doi.org/10.3389/fnins.2021.682172 |
| PubMed: | View item in PubMed |
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