A universal phase-plane model for in vivo protein aggregation

Neurodegenerative diseases are driven by the accumulation of protein aggregates in the brain of affected individuals. The aggregation behavior in vitro is well understood and driven by the equilibration of a super-saturated protein solution to its aggregated equilibrium state. However, the situation is altered fundamentally in living systems, where active processes consume energy to remove aggregates. It remains unclear how and why cells transition from a state with predominantly monomeric protein, which is stable over decades, to one dominated by aggregates. Here, we develop a simple but universal theoretical framework to describe cellular systems that include both aggregate formation and removal. Using a two-dimensional phase-plane representation, we show that the interplay of aggregate formation and removal generates cell-level bistability, with a bifurcation structure that explains both the emergence of disease and the effects of therapeutic interventions. We explore a wide range of aggregate formation and removal mechanisms and show that phenomena such as seeding arise robustly when a minimal set of requirements on the mechanism are satisfied. By connecting in vitro aggregation mechanisms to changes in cell state, our framework provides a general conceptual link between molecular-level therapeutic interventions and their impact on disease progression.