Figure 3.

Mechanisms of aggregation. (a) Expanded polyglutamine without (Q₃₀) and with (htt^NTQ₃₀P₁₀K₂) Htt flanking regions attached show dramatically different aggregation kinetics. Adapted from Sivanandam et al.⁷⁷ with permission from the American Chemical Society. (b) Intrinsically disordered HttEx1 can aggregate via both polyglutamine driven (top) and Htt^NT- driven mechanisms (bottom). (c) Both mechanisms yield products with the same ssNMR signals for the polyglutamine fibril core structure (see Figure 4): spectra of Q44-HttEx1 and polyglutamine peptide, D₂Q₁₅K₂. Adapted from Hoop et al.⁵⁶. (d) Length-dependent nucleus size data^96–98 show that fast aggregation of long polyglutamine is facilitated by monomeric nucleation, likely involving β-hairpin formation. (e) Schematic free energy profile of fibril formation and growth, for short and long polyglutamine, based on published nucleation and fiber elongation energy values.^96,97,99,100