期刊
FRONTIERS IN NEUROSCIENCE
卷 15, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2021.682172
关键词
Huntington's disease; aggregates; seeding; mHTT; zQ175; brain; protein misfolding; FRASE assay
资金
- CHDI Foundation, United States
- UK Dementia Research Institute (UK Medical Research Council)
- UK Dementia Research Institute (Alzheimer's Society)
- UK Dementia Research Institute (Alzheimer's Research UK)
- DFG, Germany [SFB/TRR167-2 B07]
- MRC [UKDRI-1008/1] Funding Source: UKRI
The study demonstrates the presence of seeding-competent, fibrillar mHTT aggregates in the brains of zQ175 knock-in HD mice. These findings suggest that small, fibrillar, seeding-competent mHTT structures are prominent aggregate species in the brains of zQ175 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, beta-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 similar to 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.
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