Emerging Trends in Cryo-EM-based Structural Studies of Neuropathological Amyloids

Tauopathies, synucleinopathies, Aβ amyloidosis, TDP-43 proteinopathies, and prion diseases- these neurodegenerative diseases have in common the formation of amyloid filaments rich in cross-β sheets. Cryo-electron microscopy now permits the visualization of amyloid assemblies at atomic resolution, ushering a wide range of structural studies on several of these poorly understood amyloidogenic proteins. Amyloids are polymorphic with minor modulations in reaction environment affecting the overall architecture of their assembly, making amyloids an extremely challenging venture for structure-based therapeutic intervention. In 2017, the first cryo-EM structure of tau filaments from an Alzheimer's disease-affected brain established that in vitro assemblies might not necessarily reflect the native amyloid fold. Since then, brain-derived amyloid structures for several proteins across many neurodegenerative diseases have uncovered the disease-relevant amyloid folds. It has now been shown for tauopathies, synucleinopathies and TDP-43 proteinopathies, that distinct amyloid folds of the same protein might be related to different diseases. Salient features of each of these brain-derived folds are discussed in detail. It was also recently observed that seeded aggregation does not necessarily replicate the brain-derived structural fold. Owing to high throughput structure determination, some of these native amyloid folds have also been successfully replicated in vitro. In vitro replication of disease-relevant filaments will aid development of imaging ligands and defibrillating drugs. Towards this direction, recent high-resolution structures of tau filaments with positron emission tomography tracers and a defibrillating drug are also discussed. This review summarizes and celebrates the recent advancements in structural understanding of neuropathological amyloid filaments using cryo-EM.