Prefibrillar huntingtin oligomers isolated from HD brain potently seed amyloid formation

•Conformational selection of misfolded HTT by immunopurification complements amyloidogenicity assays.•A11-reactive prefibrillar huntingtin oligomers are on the amyloid formation pathway.•A11-reactive prefibrillar huntingtin oligomers are stable in 6M guanidine. Many neurodegenerative diseases are associated with deposits of aggregated protein in the brain. The molecular pathways through which soluble proteins misfold to form amyloids and large protein aggregates often include diverse oligomeric species, only some of which progress to the amyloid state. Here we show that prefibrillar huntingtin (HTT) oligomers, isolated from Huntington’s disease (HD) affected human brain samples or mouse models, stimulate polyglutamine amyloid formation. Fibrillar HTT oligomers have been shown to be unstable under denaturing conditions and appear not to lead to amyloid formation. Here we show that prefibrillar HTT oligomers are remarkably stable and are potent seeds of polyglutamine amyloid formation. Therefore, our findings help to dissect the complex molecular pathway of HTT misfolding.