Polyphenol-Rich Cinnamon Bud Extract Affects Ataxin-3 Aggregation and Ameliorates SCA3 Phenotypes Through a Dual Anti-Amyloidogenic and Antioxidant Mechanism

Aberrant self-assembly of ataxin-3 (ATX3) into amyloid aggregates is a key pathological event in spinocerebellar ataxia type 3 (SCA3). Bioactive nutraceutical compounds, particularly polyphenols, have emerged as promising candidates for targeting protein aggregation and cellular stress responses associated with neurodegenerative disorders. Here, we investigated cinnamon bud extract as a natural source of neuroprotective molecules, focusing on its total extract (Etot) and two bioactive fractions: a polyphenol-enriched fraction (Fr. B) and a cinnamaldehyde-rich fraction (Fr. C). By integrating biochemical and biophysical techniques, we demonstrate that cinnamon-derived compounds modulate ATX3 aggregation by reducing the formation of β-sheet-rich amyloid assemblies and promoting the generation of SDS-resistant, soluble, structurally distinct, non-fibrillar species. NMR profiling identified flavonoids, cinnamaldehyde, and cinnamic acid as key ATX3-interacting molecules, supporting their contribution to the anti-amyloidogenic activity of the extract. Moreover, in a Caenorhabditis elegans SCA3 model, Etot and Fr. B improved locomotor defects and enhanced resistance to oxidative and thermal stress, indicating broader cytoprotective effects beyond direct aggregation modulation. Overall, these findings highlight cinnamon bud extract, particularly its polyphenol-rich fraction, as a promising nutraceutical source of bioactive compounds with potential neuroprotective properties and provide a basis for further investigation of nutraceutical strategies targeting polyglutamine-related neurodegenerative diseases.