The dual nature of amyloids: From pathogenic aggregates to functional biostructures

Protein aggregation is a process in which proteins misfold and accumulate into insoluble clumps. This phenomenon is at the root of over 50 human pathologies including neurodegenerative disorders as well as certain types of diabetes and cancer. When proteins aggregate, they often form amyloids—highly ordered structures characterized by layers of proteins aligned in a distinctive cross-β-sheet pattern. These amyloid fibrils are extremely stable and resistant to mechanical, chemical, and enzymatic degradation, making them difficult for the body to clear and contributing to pathology.
Historically, amyloids were exclusively linked to pathological conditions, given their association with tissue damage and cell death. However, this view has been fundamentally revised with the discovery of functional amyloids, which play beneficial roles in various organisms. These functional amyloids are deliberately formed and have been shown to participate in critical processes, such as controlled hormone storage and release, memory stabilization, and protection against environmental stressors like UV light and microbial infection. Their existence, however, raises questions on the basic biology underlying amyloid pathology. What traits differentiate toxic from functional amyloids? How do biological systems cope and minimize the harmful side effects of amyloid formation?
In this article, we review recent advances in understanding amyloid toxicity and illustrate diverse molecular mechanisms organisms use to control amyloid formation, turning a potentially harmful process into a tool for advantageous functions.