Scaling analysis reveals the mechanism and rates of prion replication in vivo

Prions consist of pathological aggregates of cellular prion protein and have the ability to replicate, causing neurodegenerative diseases, a phenomenon mirrored in many other diseases connected to protein aggregation, including Alzheimer's and Parkinson's diseases. However, despite their key importance in disease, the individual processes governing this formation of pathogenic aggregates, as well as their rates, have remained challenging to elucidate in vivo. Here we bring together a mathematical framework with kinetics of the accumulation of prions in mice and microfluidic measurements of aggregate size to dissect the overall aggregation reaction into its constituent processes and quantify the reaction rates in mice. Taken together, the data show that multiplication of prions in vivo is slower than in in vitro experiments, but efficient when compared with other amyloid systems, and displays scaling behavior characteristic of aggregate fragmentation. These results provide a framework for the determination of the mechanisms of disease-associated aggregation processes within living organisms. The kinetics of prion aggregation are now dissected in mice, revealing slower PrPSc replication in vivo than in vitro and the contribution of aggregate fragmentation.

Automated summary

Prions, consisting of pathological aggregates of cellular prion protein, have the ability to replicate and cause neurodegenerative diseases. The formation of these aggregates and their rates have been challenging to elucidate in vivo. Using a mathematical framework and microfluidic measurements in mice, the overall aggregation reaction has been dissected into constituent processes and reaction rates quantified. Results show that prion multiplication in vivo is slower than in vitro, but efficient compared with other amyloid systems, displaying scaling behavior characteristic of aggregate fragmentation. This provides a framework for understanding disease-associated aggregation processes within living organisms.