Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress

Greeshma Jain, Marina Trombetta-Lima, Irina Matlahov, Hennrique Taborda Ribas, Tingting Chen, Raffaella Parlato, Giuseppe Portale, Amalia M. Dolga () and Patrick C. A. Wel ()
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Greeshma Jain: University of Groningen
Marina Trombetta-Lima: University of Groningen
Irina Matlahov: University of Groningen
Hennrique Taborda Ribas: University of Groningen
Tingting Chen: University of Groningen
Raffaella Parlato: University of Groningen
Giuseppe Portale: University of Groningen
Amalia M. Dolga: University of Groningen
Patrick C. A. Wel: University of Groningen

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Huntington’s disease (HD) is a neurodegenerative disorder in which mutated fragments of the huntingtin protein (Htt) undergo misfolding and aggregation. Since aggregated proteins can cause cellular stress and cytotoxicity, there is an interest in the development of small molecule aggregation inhibitors as potential modulators of HD pathogenesis. Here, we study how a polyphenol modulates the aggregation mechanism of huntingtin exon 1 (HttEx1) even at sub-stoichiometric ratios. Sub-stoichiometric amounts of curcumin impacted the primary and/or secondary nucleation events, extending the pre-aggregation lag phase. Remarkably, the disrupted aggregation process changed both the aggregate structure and its cell metabolic properties. When administered to neuronal cells, the ‘break-through’ protein aggregates induced significantly reduced cellular stress compared to aggregates formed in absence of inhibitors. Structural analysis by electron microscopy, small angle X-ray scattering (SAXS), and solid-state NMR spectroscopy identified changes in the fibril structures, probing the flanking domains in the fuzzy coat and the fibril core. We propose that changes in the latter relate to the presence or absence of polyglutamine (polyQ) β-hairpin structures. Our findings highlight multifaceted consequences of small molecule inhibitors that modulate the protein misfolding landscape, with potential implications for treatment strategies in HD and other amyloid disorders.

Date: 2025
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DOI: 10.1038/s41467-025-58691-9

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