Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains.

Aged Cryoelectron Microscopy Female Humans Male Middle Aged Protein Aggregation, Pathological / metabolism Protein Processing, Post-Translational Tauopathies / metabolism tau Proteins / chemistry
Alzheimer's disease acetylation corticobasal degeneration cryo-EM integrated structural biology posttranslational modifications tau strains tauopathy templated seeding ubiquitination

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
20 02 2020
Historique:
received: 22 11 2019
revised: 23 12 2019
accepted: 21 01 2020
pubmed: 8 2 2020
medline: 25 8 2020
entrez: 8 2 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2020.01.027 PMID: 32032505 PMC: PMC7491959
pubmed: 32032505
pii: S0092-8674(20)30108-2
doi: 10.1016/j.cell.2020.01.027
pmc: PMC7491959
mid: NIHMS1569114
pii:
doi:

Substances chimiques

tau Proteins 0

Types de publication

Case Reports Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

633-644.e12

Subventions

Organisme : NINDS NIH HHS
ID : R35 NS097273
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG062171
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061800
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103310
Pays : United States
Organisme : NCRR NIH HHS
ID : P41 RR001209
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061357
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS088689
Pays : United States
Organisme : NIGMS NIH HHS
ID : U24 GM116792
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG056151
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS084974
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR023057
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS100693
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS110438
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG053960
Pays : United States
Organisme : NIH HHS
ID : S10 OD018111
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG062077
Pays : United States
Organisme : NINDS NIH HHS
ID : P01 NS099114
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046161
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : ErratumIn

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Tamta Arakhamia (T)

Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA.

Christina E Lee (CE)

Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA.

Yari Carlomagno (Y)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Duc M Duong (DM)

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

Sean R Kundinger (SR)

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

Kevin Wang (K)

Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA.

Dewight Williams (D)

John M. Cowley Center for High Resolution Electron Microscopy, Arizona State University, Tempe, AZ 85287, USA.

Michael DeTure (M)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Dennis W Dickson (DW)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Casey N Cook (CN)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Nicholas T Seyfried (NT)

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.

Leonard Petrucelli (L)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: petrucelli.leonard@mayo.edu.

Anthony W P Fitzpatrick (AWP)

Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: anthony.fitzpatrick@columbia.edu.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Posttranslational Modifications Mediate the...
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Cryomicroscopie électronique › Posttranslational Modifications Mediate the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Posttranslational Modifications Mediate the...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Posttranslational Modifications Mediate the...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Agrégation pathologique de protéines › Posttranslational Modifications Mediate the...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Posttranslational Modifications Mediate the...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Tauopathies › Posttranslational Modifications Mediate the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Protéines associées aux microtubules › Protéines tau › Posttranslational Modifications Mediate the...