Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Arakhamia, Tamta; Lee, Christina; Carlomagno, Yari; Kumar, Mukesh; Duong, Duc M.; Wesseling, Hendrik; Kundinger, Sean R.; Wang, Kevin; Williams, Dewight; DeTure, Michael; Dickson, Dennis W.; Cook, Casey; Seyfried, Nicholas T.; Petrucelli, Leonard; Steen, Judith A.; Fitzpatrick, Anthony W P

doi:10.1016/j.cell.2021.11.029

Cited by 57 publications

(91 citation statements)

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“…For the second hexapeptide motif 306 VQIVYK 311 , we also found that about 8% of the models are within 1.0 Å C α RMSD of the X-ray structure (PDB: 2ON9 76 ) (Figure 3B,D), about 2.5 times more than what would be expected for random hexapeptide segments. We found similar consistency for the second hexapeptide motif with the structures of tau fibrils (Figure S9), as formed in Alzheimer’s disease (PDB: 5O30, 79 5O3T, 79 6HRE, 80 6HRF 80 ), CBD (6TJO, 78 6VI3 81 ), Pick’s disease (6GX5 82 ) and chronic traumatic encephalopathy (6NWP 83 ). Experiments on tau K18 in solution suggest that these motifs should be partially in extended conformations, consistent with our ensemble.…”

Section: Resultssupporting

confidence: 70%

Global Structure of the Intrinsically Disordered Protein Tau Emerges from its Local Structure

Stelzl

Pietrek

Holla

et al. 2021

Preprint

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The paradigmatic disordered protein tau plays an important role in neuronal function and neurodegenerative diseases. To disentangle the factors controlling the balance between functional and disease-associated conformational states, we build a structural ensemble of the tau K18 fragment containing the four pseudorepeat domains involved in both microtubule binding and amyloid fibril formation. We assemble 129-residue-long tau K18 chains at atomic resolution from an extensive fragment library constructed with molecular dynamics simulations. We introduce a reweighted hierarchical chain growth (RHCG) algorithm that integrates experimental data reporting on the local structure into the assembly process in a systematic manner. By combining Bayesian ensemble refinement with importance sampling, we obtain well-defined ensembles and overcome the problem of exponentially varying weights in the integrative modeling of long-chain polymeric molecules. The resulting tau K18 ensembles capture nuclear magnetic resonance (NMR) chemical shift and J-coupling measurements. Without further fitting, we achieve excellent agreement with measurements of NMR residual dipolar couplings. The good agreement with experimental measures of global structures such as singlemolecule Förster resonance energy transfer (FRET) efficiencies is improved further by ensemble refinement. By comparing wild-type and mutant ensembles, we show that pathogenic single-point P301 mutations shift the population from the turn-like conformations of the functional microtubule-bound state to the extended conformations of disease-associated tau fibrils. RHCG thus provides us with an atomically resolved view of the population equilibrium between functional and aggregation-prone states of tau K18, and demonstrates that global structural characteristics of this intrinsically disordered protein emerge from its local structure.

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Section: Resultssupporting

confidence: 70%

Global Structure of the Intrinsically Disordered Protein Tau Emerges from its Local Structure

Stelzl

Pietrek

Holla

et al. 2021

Preprint

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“…Tau filaments consist of a structured core made mostly of the repeat domain, with less structured N- and C-terminal regions forming the fuzzy coat ( Goedert et al, 1988 ; Wischik et al, 1988a ). Previously, we and others used electron cryo-microscopy (cryo-EM) to determine the atomic structures of the cores of tau filaments extracted from the brains of individuals with a number of neurodegenerative diseases ( Fitzpatrick et al, 2017 ; Falcon et al, 2018a ; Falcon et al, 2019 ; Falcon et al, 2019 ; Arakhamia et al, 2021 ; Zhang et al, 2020 ; Shi et al, 2021 ). Whereas, tau filaments from different individuals with a given disease share the same structures, different diseases tend to be characterised by distinct tau folds.…”

Section: Introductionmentioning

confidence: 99%

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

Lövestam

Koh

Knippenberg

et al. 2022

eLife

177

166

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Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

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“…Acetylation has been described as a pathogenic post-translational modification of tau in brains from AD 7,8 and related tauopathies patients 5,6,9,10 . Recently, acetylation sites have been precisely mapped onto the Cryo-EM structure of tau filaments from patients' brain tissue 11 . Tau acetylation reduces its binding to microtubules, promotes tau fibrillization, reduces tau degradation 5,9 , and contributes to tau-mediated synaptic toxicity 12 .…”

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confidence: 99%

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice

et al. 2021

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Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.

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Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Cited by 57 publications

References 0 publications

Global Structure of the Intrinsically Disordered Protein Tau Emerges from its Local Structure

Global Structure of the Intrinsically Disordered Protein Tau Emerges from its Local Structure

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice

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