In:
Frontiers in Neuroscience, Frontiers Media SA, Vol. 15 ( 2021-6-22)
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 ( & gt;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 of Medium:
Online Resource
ISSN:
1662-453X
DOI:
10.3389/fnins.2021.682172
DOI:
10.3389/fnins.2021.682172.s001
DOI:
10.3389/fnins.2021.682172.s002
DOI:
10.3389/fnins.2021.682172.s003
DOI:
10.3389/fnins.2021.682172.s004
DOI:
10.3389/fnins.2021.682172.s005
DOI:
10.3389/fnins.2021.682172.s006
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2021
detail.hit.zdb_id:
2411902-7
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