Figure 2.

Disassembly models proposed for the human disaggregase. Two depolymerization models have been proposed for the amyloid disassembly activity of the human disaggregase machinery. The first one established that disaggregation was expected to synchronously decrease the length at a similar rate in all fibrils, regardless of their size (a). A change in paradigm has recently been put forward, considering the disassembly as an asynchronous process (b). In this model, solubilization is not interpreted as a population of aggregates with decreasing size over time, instead being considered as a population with a decreasing number of aggregates over time. This mechanism especially applies for toxic oligomers/short fibrils, being eliminated by the chaperones one by one rather than progressively reducing their size. Disassembly starts with the destabilization of the fibril tips and rapidly progresses to completion through protofilament unzipping and depolymerization, without accumulation of new harmful oligomeric intermediates (c). This mechanism is hampered for large fibrils due to their increased stability and reduced number of ends, biasing the human disaggregase activity toward small aggregate species, avoiding their toxicity and growth into less tractable species.