Probing the Dynamic Landscape: From Static to Time-Resolved X-Ray Absorption Spectroscopy to Investigate Copper Redox Chemistry in Neurodegenerative Disorders

Copper (Cu), with its ability to exist in various oxidation states, notably Cu(I) and Cu(II), plays a crucial role in diverse biological redox reactions. This includes its involvement in pathways associated with oxidative stress in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Transmissible Spongiform Encephalopathies. This paper offers an overview of X-ray Absorption Spectroscopy (XAS) studies designed to elucidate the interactions between Cu ions and proteins or peptides associated with these neurodegenerative diseases. The emphasis lies on XAS specificity, revealing the local coordination environment, and on its sensitivity to Cu oxidation states. Furthermore, the paper focuses on XAS applications targeting the characterization of intermediate reaction states and explores the opportunities arising from recent advancements in time-resolved XAS at ultrabright synchrotron and Free Electron Laser radiation sources. Time-resolved X-ray Absorption Spectroscopy will be the camcorder for capturing atomic resolution molecular movies. The key players in these movies are Cu(I) and Cu(II) ions, which, when complexed with proteins and peptides associated with neurodegenerative diseases, can act as redox agents with potential pathogenic implications. image