Prion protein orchestrates liquid-liquid phase separation with copper

In a study published in Scientists progressResearchers from the Federal University of Rio de Janeiro (UFRJ) and the German Center for Neurodegenerative Diseases (DZNE-Berlin) have shed light on the complex dance between the prion protein and copper ions in the pathophysiology of living cells.

The research paves the way for potential treatments targeting copper-bound prion protein clusters to prevent abnormal solid formation and mitigate neurodegenerative consequences.

Like oil droplets in water, cells harbor membrane organelles that play a crucial role in cellular function. The research contributes to the understanding of a new layer of complexity with the existence of membrane-less organelles or condensates formed by phase separation, which are protein-rich assemblies with unique liquid properties and dynamic functions. Notably, proteins linked to neurodegenerative diseases undergo phase separation, suggesting a potential link between liquid condensates and their subsequent aggregation.

The prion protein (PrP), associated with fatal brain diseases such as “mad cow” disease, has long been known to interact with copper ions in brain cells. Led by Mariana Do Amaral, a graduate student under the supervision of Professor Yraima Cordeiro (UFRJ) and Professor Susanne Wegmann (DZNE-Berlin), the study demonstrates that PrP can form dynamic liquid condensates on the surface of cells, potentially acting as trappers of excessive substances. copper ions.

Do Amaral, the first author of the paper, explains: “For over 20 years, research has hinted at the binding of copper to PrP and its role in abnormal folding. Our hypothesis was that PrP acts as a copper buffer via liquid-liquid phase separation, thereby protecting cells. due to excess copper.

The results highlight the biological importance of liquid-liquid phase separation in the regulation of copper homeostasis by PrP. The dynamic nature of PrP condensates, accumulating copper ions, suggests a finely tuned mechanism. Intriguingly, exposure to oxidative stress, a common phenomenon in diseased or aged brains, led to a transition from liquid to solid, resembling clumps associated with neurodegeneration.

This study not only deepens our understanding of prion diseases, but also paves the way for potential interventions targeting copper-bound prion protein condensates to prevent abnormal solid formation and mitigate neurodegenerative consequences.

The research used advanced biophysical techniques including X-ray photon correlation spectroscopy (XPCS) at the New Brazilian Synchrotron Light Source (Sirius-LNLS) and recovery of fluorescence from living cells after photobleaching at the Charité-LNLS. Medical University of Berlin.