Biological Amyloids Chemically Damage DNA

Journal article, 2025

Amyloid fibrils are protein polymers noncovalently assembled through beta-strands arranged in a cross-beta structure. Biological amyloids were considered chemically inert until we and others recently demonstrated their ability to catalyze chemical reactions in vitro. To further explore the functional repertoire of amyloids, we here probe if fibrils of alpha-synuclein (alpha S) display chemical reactivity toward DNA. We demonstrate that alpha S amyloids bind DNA at micromolar concentrations in vitro. Using the activity of DNA repair enzymes as proxy for damage, we unravel that DNA-amyloid interactions promote chemical modifications, such as single-strand nicks, to the DNA. Double-strand breaks are also evident based on nanochannel analysis of individual long DNA molecules. The amyloid fold is essential for the activity as no DNA chemical modification is detected with alpha S monomers. In a yeast cell model, there is increased DNA damage when alpha S is overexpressed. Chemical perturbation of DNA adds another chemical reaction to the set of activities emerging for biological amyloids. Since alpha S amyloids are also found in the nuclei of neuronal cells of Parkinson's disease (PD) patients, and increased DNA damage is a hallmark of PD, we propose that alpha S amyloids contribute to PD by direct chemical perturbation of DNA.