pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers
Abstract
Oligomers formed en route to amyloid fibrils are thought to be the perpetrators of toxicity in many amyloid disorders. How amyloid fibrils contribute to disease, however, is less clear. Here, using β2-micoglobulin (β2m) as a model system, we show that the stability of amyloid fibrils is highly pH-dependent, with mild acidification enhancing the formation of fibril-derived nonnative oligomers that disrupt membranes and alter cellular function. Enhancing fibril stability by incubation with the molecular chaperone, hsp70, or by cross-linking, protects against fibril-induced membrane disruption and cellular dysfunction. The results highlight the importance of pH in determining fibril stability and suggest that uptake of fibrils into acidic cellular compartments may contribute to amyloid disease by pH-induced molecular shedding of toxic species.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- May 2015
- DOI:
- 10.1073/pnas.1423174112
- Bibcode:
- 2015PNAS..112.5691T