Do amyloid oligomers act as traps for misfolded proteins? A hypothesis.

Mounting evidence points to soluble peptide oligomers as the primary agents in various amyloid and prion diseases. Multiple mechanisms appear to contribute to the cytotoxic effects of these oligomers. Here, an additional, general mechanism is proposed - that soluble amyloid peptide oligomers serve as "all-purpose"beta strands that can interact with transiently unfolded or nascent proteins where interior beta-sheet edges are exposed. The proteins, trapped in misfolded states through this interaction, become substrates for ubiquitination, targeting them for proteasomal degradation. The increased load of ubiquitinated proteins could contribute to the impairment of the ubiquitin/proteasome system (UPS) seen in many amyloid-related diseases. This "misfolding trap" mechanism could be especially stressful in the endoplasmic reticulum, where the amyloid oligomers would compete with chaperones for nascent beta-sheet proteins. If the bound amyloid oligomer dissociates at some point after the misfolded protein is committed to the UPS pathway, the oligomer could then repeat the process, adding a catalytic aspect to the misfolding mechanism. Direct proof of this proposed mechanism requires detection of amyloid oligomer-beta-sheet protein complexes, and a co-immunoprecipitation experiment is proposed. This hypothesis supports therapies that increase amyloid oligomer degradation or sequestration, as well as therapies that upregulate chaperone activity, for combating amyloid-related diseases.