Assessing the causes and consequences of co-polymerization in amyloid formation

Abstract

How, and why, different proteins form amyloid fibrils is most often studied in vitro using a single purified protein sequence. However, many amyloid diseases involve co-aggregation of different protein species, including proteins with/without post-translational modifications (e.g., different strains of PrP), proteins of different length (e.g., β₂-microglobulin and ΔN6, Aβ40, and Aβ42), sequence variants (e.g., Aβ and Aβ_ARC), and proteins from different organisms (e.g., bovine PrP and human PrP). The consequences of co-aggregation of different proteins upon the structure, stability, species transmission and toxicity of the resulting amyloid aggregates is discussed here, including the role of co-aggregation in expanding the repertoire of oligomeric and fibrillar structures and how this can affect their biological and biophysical properties.

Keywords: :

• amyloid
• fibril
• seeding
• heteropolymers
• polymorph
• strain

This article refers to:

10.4161/pri.26415

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by Medical Research Council Grant G0900958. We thank the Radford group for helpful discussions and critical reading of the manuscript.

Note Added in Proof

Recent work has shown that a specific and transient protofibrillar species of Abeta42, with a novel triple helical structure, is the most potent aggregate involved in the interaction between PrP and Abeta.⁶⁶ This works supports the importance of structure for influencing amyloid interactions between different proteins.