Kinetic Mechanism of Substoichiometric Inhibition of Huntingtin Exon-1 Protein Aggregation by Selenium Nanoparticles

Accumulation of huntingtin exon-1 protein (htt^ex1) fibrils within neurons occurs when the polyglutamine region exceeds ≈35 residues and is responsible for Huntington disease, a fatal neurodegenerative condition. Recent work has shown that selenium nanoparticles (SeNP) are protective against neurodegeneration. Herein, the mechanistic basis for SeNP modulation of htt^ex1 aggregation is explored. Fibril formation of htt^ex1 entails two distinct processes on timescales differing by many orders of magnitude: prenucleation oligomerization on the microsecond timescale to generate a low population of transient tetramers that undergo slow (hours timescale) unimolecular conversion into elongation-competent nuclei, followed by elongation and secondary nucleation. Using NMR spectroscopy, fluorescence immunostaining, and transmission electron microscopy, the interaction of SeNPs with two htt^ex1 protein constructs, htt^ex1Q₇ and htt^ex1Q₃₅ containing 7 and 35 glutamine repeats, respectively, is studied. htt^ex1Q₇ undergoes transient prenucleation tetramerization but remains largely monomeric over a period of weeks, while htt^ex1Q₃₅ forms fibrils within a period of hours. It is shown that SeNPs reduce the rate of fibril formation substoichiometrically with respect to monomer by selectively targeting and binding with nanomolar affinity to the extendable ends of elongation-competent species of htt^ex1Q₃₅, thereby reducing the pool of free extendable ends.