Biological\nAmyloids Chemically Damage DNA

Amyloid fibrils are protein polymers noncovalently assembled\nthrough\nβ-strands arranged in a cross-β structure. Biological\namyloids were considered chemically inert until we and others recently\ndemonstrated their ability to catalyze chemical reactions in vitro.\nTo further explore the functional repertoire of amyloids, we here\nprobe if fibrils of α-synuclein (αS) display chemical\nreactivity toward DNA. We demonstrate that αS amyloids bind\nDNA at micromolar concentrations in vitro. Using the activity of DNA\nrepair enzymes as proxy for damage, we unravel that DNA-amyloid interactions\npromote chemical modifications, such as single-strand nicks, to the\nDNA. Double-strand breaks are also evident based on nanochannel analysis\nof individual long DNA molecules. The amyloid fold is essential for\nthe activity as no DNA chemical modification is detected with αS\nmonomers. In a yeast cell model, there is increased DNA damage when\nαS is overexpressed. Chemical perturbation of DNA adds another\nchemical reaction to the set of activities emerging for biological\namyloids. Since αS amyloids are also found in the nuclei of\nneuronal cells of Parkinson’s disease (PD) patients, and increased\nDNA damage is a hallmark of PD, we propose that αS amyloids\ncontribute to PD by direct chemical perturbation of DNA.