Huntington’s disease is a fatal neurodegenerative disease arising from the presence of 36 or more CAG repeats within exon 1 of the Huntingtin (htt) gene, resulting in expansion of the polyglutamine domain that lies immediately downstream of the 16-residue N-terminal amphiphilic sequence (httNT) of the huntingtin protein. The presence of a long polyglutamine stretch results in the rapid formation of polymorphic fibrils, the rate of which is modulated by the presence of flanking regions (httNT and the proline rich domain C-terminal to the polyglutamine sequence). In general, adsorption of fibril forming proteins and peptides on the surface of nanoparticles enhances aggregation and fibril formation by increasing the local peptide concentration and hence the probability of forming a critical initiation nucleus. Titanium oxide nanoparticles (TiO2 NPs) are unique as they possess photo-catalytic properties that generate reactive oxygen species upon UV irradiation. Here we investigate the interaction between TiO2 NPs and huntingtin peptides comprising the N-terminal amphiphilic domain without (httNT) or with (httNTQ10) a ten-residue C-terminal polyglutamine tract by solution NMR spectroscopy. TiO2 NPs decrease aggregation of httNTQ10 by catalyzing the irreversible oxidation of Met7 to a sulfoxide, thereby preventing fibril formation by reducing the concentration of the aggregation-competent, native reduced form of httNTQ10. The oxidation agent is hydrogen peroxide generated on the surface of the TiO2 NPs either by UV irradiation or at low steady-state levels in the dark. The binding kinetics of non-aggregating httNT to TiO2 NPs is characterized by quantitative analysis of 15N dark state exchange saturation transfer (DEST) and lifetime line broadening (ΔR2) data. Binding involves a sparsely-populated intermediate that experiences hindered rotational diffusion relative to the free state. Catalysis of methionine oxidation within the N-terminal domain of the huntingtin protein may potentially provide a strategy for delaying the onset of Huntington’s disease.

TiO2 nanoparticles catalyze oxidation of Huntingtin exon 1-derived peptides impeding aggregation: Quantitative NMR study of binding and kinetics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.