Scaling analysis reveals the mechanism and rates of prion replication in vivo.
Cohen, Samuel IA
Dobson, Christopher M
Nature structural & molecular biology
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Meisl, G., Kurt, T., Condado-Morales, I., Bett, C., Sorce, S., Nuvolone, M., Michaels, T., et al. (2021). Scaling analysis reveals the mechanism and rates of prion replication in vivo.. Nature structural & molecular biology, 28 (4), 365-372. https://doi.org/10.1038/s41594-021-00565-x
Prions consist of pathological assemblies of normal cellular prion protein and cause infectious neurodegenerative diseases, a phenomenon mirrored in many other prion-like neurodegenerative 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 to other amyloid systems, and displays scaling behaviour characteristic of aggregate fragmentation. These results provide a framework for the determination of the mechanisms of disease-associated aggregation processes within living organisms.
Animals, Humans, Mice, Parkinson Disease, Alzheimer Disease, Amyloid, Prions, Models, Theoretical, Protein Aggregation, Pathological
European Research Council (337969)
External DOI: https://doi.org/10.1038/s41594-021-00565-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/317625
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