The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Aggregates

Neurogenerative diseases are characterized by diverse protein aggregates with a variety of microscopic morphologic features. Although ultrastructural studies of human neurodegenerative disease tissues have been conducted since the 1960s, only recently have near-atomic resolution structures of neurodegenerative disease aggregates been described. Solid-state nuclear magnetic resonance spectroscopy and X-ray crystallography have provided near-atomic resolution information about in vitro aggregates but pose logistical challenges to resolving the structure of aggregates derived from human tissues. Recent advances in cryo-electron microscopy (cryo-EM) have provided the means for near-atomic resolution structures of tau, amyloid-β (Aβ), α-synuclein (α-syn), and transactive response element DNA-binding protein of 43 kDa (TDP-43) aggregates from a variety of diseases. Importantly, in vitro aggregate structures do not recapitulate ex vivo aggregate structures. Ex vivo tau aggregate structures indicate individual tauopathies have a consistent aggregate structure unique from other tauopathies. α-syn structures show that even within a disease, aggregate heterogeneity may correlate to disease course. Ex vivo structures have also provided insight into how posttranslational modifications may relate to aggregate structure. Though there is less cryo-EM data for human tissue-derived TDP-43 and Aβ, initial structural studies provide a basis for future endeavors. This review highlights structural variations across neurodegenerative diseases and reveals fundamental differences between experimental systems and human tissue derived protein inclusions.