Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted

The first exon of the huntingtin protein (HTTex1) important in Huntington's disease (HD) can form cross-beta fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-beta fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease. Huntingtin exon-1 (HTTex1) consists of a N-terminal N17 domain, the disease causing polyQ domain and a C-terminal proline-rich domain (PRD). Here, the authors combine electron paramagnetic resonance (EPR), solid-state NMR with other biophysical method to characterise the structural differences of various HTTex1 fibril types with different toxicity and find that the dynamics and entanglement of the PRD domain differs among them and that the HTTex1 fibrils can be interconverted.

Automated summary

The research identified structural differences among different types of HTTex1 fibrils, focusing on the dynamics and entanglement of the PRD domain, which can be interconverted and have varying toxicities. The study also showed that low entanglement toxic fibrils have higher affinities for protein interactors, making them more effective seeds for HTTex1 in cells.