Fig. 5: Models for HttEx1 fibril structure and assembly.

a Existing models of Q44-HttEx1 multi-filament ‘wide’ fibrils (left) and a single-filament ‘narrow’ fibrils (right)¹⁹. Both models show a β-sheet core formed by polyQ segments in a β-hairpin fold. b Hypothetical models of Q32-HttEx1 fibrils formed in absence of curcumin, which match the observed TEM core width: double-filament fibrils with β-hairpins (left) or single-filament fibrils without (right). The ssNMR data show flexible PRD which is not consistent with the former model. c Hypothetical models of Q32-HttEx1 fibrils formed in presence of curcumin. Left model assumes an extended β-strand (no β-hairpin), but the predicted core diameter does not match TEM width. The model on the right shows the polyQ segment as a single filament featuring β-hairpins. d Schematic of the complex HttEx1 aggregation pathway, with competing mechanisms without (top) and with β-hairpin formation (bottom). The former pathway is dominant in absence of curcumin, but is inhibited by curcumin. Observed ‘break-through’ fibril formation (upon curcumin inhibition) results in fibril cores with a narrower width, consistent with the presence of β-hairpins. Panel a, b was adapted from ref. ¹⁹ under its CC open-access license.