Figure 4.

The two faces of the Hsc70-based human disaggregase. In a healthy cell state (low aggregate:disaggregase ratio; green arrow), the human disaggregase rapidly disassemble seed-competent intermediates into the native state, avoiding their toxic effect. Under aggregation stress (high aggregate:disaggregase ratio; red arrows), the disaggregase machinery becomes overwhelmed and the chaperone-mediated disassembly of seed-competent intermediates slows down or is even halted, increasing their life-span. Thus, these species are stable enough to express their toxicity via aberrant interactions with different cellular components and spreading to neighboring cells where seeded-aggregation is induced. Alternatively, oligomers can grow into large fibrils that either tend to deposit or contribute to secondary aggregation processes such as surface-catalyzed nucleation or fibril fragmentation, functioning as a pool of new seed-competent oligomers. The overwhelmed human disaggregase could also contribute to the production of new toxic intermediates in an attempt to disassemble fibrils due to their incomplete depolymerization/fragmentation. Solid arrows represent processes in which the Hsc70-based machinery is actively implicated, while dashed ones occur regardless of its disaggregase activity.