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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-\u03b2 (A\u03b2), \u03b1-synuclein (\u03b1-syn), and transactive response element DNA-binding protein of 43\u2009kDa (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. \u03b1-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 A\u03b2, 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.<\/jats:p>","DOI":"10.1093\/jnen\/nlab039","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T12:54:12Z","timestamp":1620651252000},"page":"514-529","source":"Crossref","is-referenced-by-count":27,"title":["The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Aggregates"],"prefix":"10.1093","volume":"80","author":[{"given":"Benjamin C","family":"Creekmore","sequence":"first","affiliation":[{"name":"From the Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania, USA"},{"name":"Graduate Program in Biochemistry and Molecular Biophysics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania, 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