Horvath Istvan, Aning Obed Akwasi, Kk Sriram, Rehnberg Nikita, Chawla Srishti, Molin Mikael, Westerlund Fredrik, Wittung-Stafshede Pernilla
Department of Life Sciences, Chalmers University of Technology, 412 96 Gothenburg, Sweden.
ACS Chem Neurosci. 2025 Feb 5;16(3):355-364. doi: 10.1021/acschemneuro.4c00461. Epub 2025 Jan 9.
Amyloid fibrils are protein polymers noncovalently assembled through β-strands arranged in a cross-β 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 α-synuclein (αS) display chemical reactivity toward DNA. We demonstrate that αS 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 αS monomers. In a yeast cell model, there is increased DNA damage when αS is overexpressed. Chemical perturbation of DNA adds another chemical reaction to the set of activities emerging for biological amyloids. Since αS 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 αS amyloids contribute to PD by direct chemical perturbation of DNA.
淀粉样纤维是通过排列成交叉β结构的β链非共价组装而成的蛋白质聚合物。在我们和其他研究人员最近证明生物淀粉样蛋白具有体外催化化学反应的能力之前，它们一直被认为是化学惰性的。为了进一步探索淀粉样蛋白的功能范围，我们在此探究α-突触核蛋白（αS）纤维是否对DNA具有化学反应性。我们证明αS淀粉样蛋白在体外以微摩尔浓度结合DNA。以DNA修复酶的活性作为损伤的指标，我们发现DNA-淀粉样蛋白相互作用会促进DNA发生化学修饰，如单链切口。基于对单个长DNA分子的纳米通道分析，双链断裂也很明显。淀粉样折叠对于该活性至关重要，因为用αS单体未检测到DNA化学修饰。在酵母细胞模型中，αS过表达时DNA损伤增加。DNA的化学扰动为生物淀粉样蛋白出现的一系列活性增加了另一种化学反应。由于在帕金森病（PD）患者的神经元细胞核中也发现了αS淀粉样蛋白，并且DNA损伤增加是PD的一个标志，我们提出αS淀粉样蛋白通过对DNA的直接化学扰动导致PD。
