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

Abstract

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 mea-

In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease

“…Moreover, neurons may be more effective at preventing replication when it occurs more slowly so that protective mechanisms are less easily overwhelmed. By contrast, we recently determined the replication rate of prions in mice (27) and found that it proceeds much faster in vitro than in vivo, indicating that in other mouse models, the effect of processes to inhibit aggregation in vivo can be much more pronounced than what we find in the mouse model analyzed here. Notably, the replication rate of prions in mice determined by Meisl et al (27) is very similar to that of tau in P301S mice determined here.…”

“…By contrast, we recently determined the replication rate of prions in mice (27) and found that it proceeds much faster in vitro than in vivo, indicating that in other mouse models, the effect of processes to inhibit aggregation in vivo can be much more pronounced than what we find in the mouse model analyzed here. Notably, the replication rate of prions in mice determined by Meisl et al (27) is very similar to that of tau in P301S mice determined here. This similarity may be due to the fact that the choice of the mutant and the level of protein expression is optimized for a life span of several months in the mouse models.…”

Secondary Nucleation and the Conservation of Structural Characteristics of Amyloid Fibril Strains

“…Perhaps the physico-chemical environment in vivo allows only a limited number of strains to form de novo, and hence faithful strain transmission is not required in order to maintain strain homogeneity. There is, however, recent evidence that points toward the possibility that in cases where strain propagation is observed, most notably the mammalian prions, fragmentation could be the mechanism responsible for this propagation (Meisl et al, 2021). More research is needed to establish the degree of strain homogeneity in additional in vivo settings and to investigate the strain propagation of secondary nucleation for additional proteins and solution conditions that mimic in vivo conditions as closely as possible.…”

Propagation and Dissemination Strategies of Transmissible Spongiform Encephalopathy Agents in Mammalian Cells

“…Following synthesis and glycosylation in the endoplasmic reticulum and Golgi, mature PrP C is present on the cell surface. PrP C is mainly found in rafts, membrane microdomains enriched in phospholipids and cholesterol [ 21 , 22 ]. Some PrP C molecules undergo proteolytic cleavage or membrane shedding (reviewed in [ 23 ]).…”