Heterotypic amyloid interactions: Clues to polymorphic bias and selective cellular vulnerability?

The number of atomic-resolution structures of disease-associated amyloids has greatly increased in recent years. These structures have confirmed not only the polymorphic nature of amyloids but also the association of specific polymorphs to particular proteinopathies. These observations are strengthening the view that amyloid polymorphism is a marker for specific pathological subtypes (e.g. in tauopathies or synucleinopathies). The nature of this association and how it relates to the selective cellular vulnerability of amyloid nucleation, propagation and toxicity are still unclear. Here, we provide an overview of the mechanistic insights provided by recent patient-derived amyloid structures. We discuss the framework organisation of amyloid polymorphism and how heterotypic amyloid interactions with the physiological environment could modify the solubility and assembly of amyloidogenic proteins. We conclude by hypothesising how such interactions could contribute to selective cellular vulnerability.

Automated summary

The number of disease-associated amyloid structures at atomic resolution has increased significantly in recent years. These structures have confirmed the polymorphic nature of amyloids and their association with specific proteinopathies. The exact nature and relationship of this association with the selective vulnerability of amyloid nucleation, propagation, and toxicity are still unknown. However, recent patient-derived amyloid structures have provided mechanistic insights, discussing the framework organization of amyloid polymorphism and how heterotypic amyloid interactions with the physiological environment could modify the solubility and assembly of amyloidogenic proteins.