Speaker
Description
The molecular chaperone Hsp104 is essential for the propagation of the yeast prion [PSI+], yet the precise mechanism by which it remodels prion aggregates remains contested. A leading alternative to the fragmentation model - in which Hsp104 internally severs amyloid fibers to generate new seeds - is the trimming hypothesis, which proposes that Hsp104 acts as a distinct enzymatic activity that removes monomers exclusively from fiber ends. We present a combined deterministic and stochastic modeling framework to critically evaluate these competing mechanisms. Our deterministic models allow systematic exploration of parameter space to identify regimes consistent with observed prion dynamics, while our stochastic framework captures population-level heterogeneity in aggregate inheritance across cell divisions. We show that if trimming represents a qualitatively distinct Hsp104 activity selectively activated under guanidine treatment, this mechanism is inconsistent with observed data. In contrast, interpreting end-proximal breakage as a modest positional bias within a general fragmentation framework remains fully consistent with all observations. Our results support the conclusion that reduced fragmentation activity under guanidine, rather than a separate trimming mechanism, is the parsimonious explanation for existing experimental evidence.
