Huntington’s disease is a fatal neurodegenerative condition arising from polyglutamine expansion within the Huntingtin protein leading to fibril accumulation in neurons. The initial multimerization events occur on the submillisecond timescale and involve sparsely populated species that can be probed at atomic resolution by NMR. Using a minimalistic construct comprising the N-terminal amphiphilic domain and seven glutamines, we uncover a branched oligomerization pathway, one leading to a tetramer comprising a dimer of coiled-coil helical dimers, and the other resulting in a nonproductive, partially helical, dimer. profilin-I, an abundant intracellular protein, that inhibits fibril formation acts by binding to the two polyproline repeats C-terminal to the polyQ region and block the productive pathway while leaving the unprodictive pathway unaffected. The results illuminate the contribution of the N-terminal amphiphilic domain in prenucleation events that precede fibril formation.

Probing initial transient oligomerization events facilitating Huntingtin fibril nucleation at atomic resolution by relaxation-based NMR

ACS Spring Meeting 2021

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