ABSTRACT

Biomolecular condensates in living cells can exhibit a complex rheology including viscoelastic and glassy behaviour. This rheological behavior of condensates was suggested to regulate polymerisation of cytoskeletal filaments and aggregation of amyloid fibrils. Here, we theoretically investigate how the rheological properties of condensates can control the formation of linear aggregates. To this end, we propose a kinetic theory for linear aggregation in coexisting phases, which accounts for the aggregate size distribution and the exchange of aggregates between inside and outside of condensates. The rheology of condensates is accounted in our model via aggregate mobilities that depend on aggregate size. We show that condensate rheology determines whether aggregates of all sizes or dominantly small aggregates are exchanged between condensate inside and outside on the time-scale of aggregation. As a result, the ratio of aggregate numbers inside to outside of condensates differs significantly. Strikingly, we also find that weak variations in the rheological properties of condensates can lead to a switch-like change of the number of aggregates. These results suggest a possible physical mechanism for how living cells could control linear aggregation in a switch-like fashion through variations in condensate rheology.

SIGNIFICANCE

The intracellular space can be organized through phase-separated condensates that often exhibit rheological properties reminiscent of complex fluids. These condensates can affect biochemical processes such as the formation of linear aggregates, in particular biofilaments or amyloids. Here, we propose a theoretical model for how condensate rheology can control the irreversible formation of linear aggregates. A key finding is that size and number of aggregates change in a switch-like fashion upon weak changes in condensate rheology. Our model paves the way to unravel the physiochemical mechanisms of how the rheology of condensates can control aberrant protein aggregation. Such mechanisms may explain how rheological changes, such as ageing or the transition to dormancy, give rise to diseases related to protein aggregation.