@article{9753279f2e2348ada40bc46788bdd57e,
title = "Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains",
abstract = "Tau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation and templated seeding of strain-specific structures associated with individual tauopathies. Here, we use cryo-electron microscopy (cryo-EM) to determine the structures of tau filaments from corticobasal degeneration (CBD) human brain tissue. Cryo-EM and mass spectrometry of tau filaments from CBD reveal that this conformer is heavily decorated with posttranslational modifications (PTMs), enabling us to map PTMs directly onto the structures. By comparing the structures and PTMs of tau filaments from CBD and Alzheimer's disease, it is found that ubiquitination of tau can mediate inter-protofilament interfaces. We propose a structure-based model in which cross-talk between PTMs influences tau filament structure, contributing to the structural diversity of tauopathy strains. Our approach establishes a framework for further elucidating the relationship between the structures of polymorphic fibrils, including their PTMs, and neurodegenerative disease. Structural and mass spectrometry-based proteomics of tau filaments, including their posttranslational modifications, from corticobasal degeneration and Alzheimer's disease point to how cross-talk between posttranslational modifications influences fibril structure, contributing to the structural diversity of tauopathy strains.",
keywords = "Alzheimer's disease, acetylation, corticobasal degeneration, cryo-EM, integrated structural biology, posttranslational modifications, tau strains, tauopathy, templated seeding, ubiquitination",
author = "Tamta Arakhamia and Lee, {Christina E.} and Yari Carlomagno and Duong, {Duc M.} and Kundinger, {Sean R.} and Kevin Wang and Dewight Williams and Michael DeTure and Dickson, {Dennis W.} and Cook, {Casey N.} and Seyfried, {Nicholas T.} and Leonard Petrucelli and Fitzpatrick, {Anthony W.P.}",
note = "Funding Information: We are exceedingly grateful to the patients and their families for their participation in this work. Human biological samples and associated data were obtained from the Mayo Clinic Brain Bank. This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorder and Stroke and the National Institute on Aging (UO1NS110438 and RF1AG056151-01A1 to A.W.P.F.; R35NS097273, U01NS110438-02, P01NS084974, P01NS099114, R01NS088689, RF1AG062077-01, RF1 AG062171-01, and U54NS100693 to L.P.; R01AG053960, R01AG061800, U01AG046161, and U01AG061357 to N.T.S.); the NSF MRI grant (1531991) for the ThermoFisher Titan Krios at the Eyring Materials center at ASU. We thank Prof. H. Zhou for use of the Titan Krios at UCLA EICN. This work was also supported by grants from the NIH (S10RR23057, S10OD018111, and U24GM116792) and the NSF (DBI-1338135 and DMR-1548924). We thank Dr. W.J. Rice for help collecting data on the Titan Krios at the NYU Langone Cryo-EM Core Facility; Dr. X. Chen and Dr. K. Song for help collecting data on the Titan Krios at the University of Massachusetts Medical School Cryo-EM Core Facility; R. Grassucci and Dr. Z. Zhang for help collecting data on the Columbia University Medical School Titan Krios housed at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy (New York Structural Biology Center) supported by grants from the Simons Foundation (349247), NYSTAR, and the NIH (GM103310); the Mayo Clinic Foundation; the Association for Frontotemporal Degeneration; the Dana Foundation; and the Cure Alzheimer's Fund. We thank Professor R.S. Mann for helpful discussions. This paper is dedicated to the memory of Professor Sir Christopher M. Dobson, F.R.S. Ph.D. advisor and mentor to A.W.P.F. A.W.P.F. N.T.S. and L.P. conceived the experiments. D.W.D. and M.D. identified patients and performed neuropathology. Y.C. purified tau filaments from CBD and AD cases. A.W.P.F. T.A. and D.W. performed cryo-EM experiments on CBD and AD samples. D.M.D. S.R.K. and N.T.S. performed and analyzed mass spectrometry experiments. A.W.P.F. T.A. and K.W. processed cryo-EM data. A.W.P.F. and C.E.L. built atomic models. A.W.P.F, T.A. C.E.L. C.N.C. and L.P. prepared the manuscript. L.P. and A.W.P.F. supervised the project. The authors declare no competing interests. Funding Information: We are exceedingly grateful to the patients and their families for their participation in this work. Human biological samples and associated data were obtained from the Mayo Clinic Brain Bank. This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorder and Stroke and the National Institute on Aging ( UO1NS110438 and RF1AG056151-01A1 to A.W.P.F.; R35NS097273 , U01NS110438-02 , P01NS084974 , P01NS099114 , R01NS088689 , RF1AG062077-01 , RF1 AG062171-01 , and U54NS100693 to L.P.; R01AG053960 , R01AG061800 , U01AG046161 , and U01AG061357 to N.T.S.); the NSF MRI grant ( 1531991 ) for the ThermoFisher Titan Krios at the Eyring Materials center at ASU. We thank Prof. H. Zhou for use of the Titan Krios at UCLA EICN. This work was also supported by grants from the NIH ( S10RR23057 , S10OD018111 , and U24GM116792 ) and the NSF ( DBI-1338135 and DMR-1548924 ). We thank Dr. W.J. Rice for help collecting data on the Titan Krios at the NYU Langone Cryo-EM Core Facility; Dr. X. Chen and Dr. K. Song for help collecting data on the Titan Krios at the University of Massachusetts Medical School Cryo-EM Core Facility; R. Grassucci and Dr. Z. Zhang for help collecting data on the Columbia University Medical School Titan Krios housed at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy (New York Structural Biology Center) supported by grants from the Simons Foundation ( 349247 ), NYSTAR , and the NIH ( GM103310 ); the Mayo Clinic Foundation ; the Association for Frontotemporal Degeneration ; the Dana Foundation ; and the Cure Alzheimer's Fund . We thank Professor R.S. Mann for helpful discussions. This paper is dedicated to the memory of Professor Sir Christopher M. Dobson, F.R.S., Ph.D. advisor and mentor to A.W.P.F. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = feb,
day = "20",
doi = "10.1016/j.cell.2020.01.027",
language = "English (US)",
volume = "180",
pages = "633--644.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}