CoChat
Sign Up
Cited by 25Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingProtein Structure and Dynamics

Disease-associated patterns of acetylation stabilize tau fibril formation

Open access
Li, Li, Nguyen, Binh A., Mullapudi, Vishruth, Li, Yang, Saelices, Lorena, Joachimiak, Lukasz A.·2023·Structure
DOI 10.1016/j.str.2023.05.020PMC PMC10527703

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has emerged. Using tau fragments, we identify patterns of acetylation that flank amyloidogenic motifs on the tau fragments that promote rapid fibril assembly. We determined a 3.9 Å cryo-EM amyloid fibril structure assembled from an acetylated tau fragment uncovering how lysine acetylation can mediate gain-of-function interactions. Comparison of the structure to an ex vivo tauopathy fibril reveals regions of structural similarity. Finally, we show that fibrils encoding disease-associated patterns of acetylation are active in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting tau aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct amyloid folds.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.str.2023.05.020

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several potential mechanisms by which GBA deficiency can impact cell function include disrupting CMA and inducing ER stress through misfolded GBA mutants.

    “In addition to disrupted lipid homeostasis and autophagy, there are several potential mechanisms by which GBA deficiency can impact cell function (Figure 4, left panel), including disrupting CMA (described in a later section), and inducing ER stress through misfolded GBA mutants.99”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [99]

    The Introduction discusses tau acetylation and mentions chaperone-mediated autophagy in relation to tau, not GBA deficiency. Searches for GBA deficiency, misfolded GBA mutants, and ER stress found no passage addressing the attributed mechanisms in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Mutant GBA binds to and interferes with normal LAMP2A function, impeding processing of CMA client proteins, particularly alpha-synuclein.

    “Second, it was recently shown that mutant glucocerebrosidase A (the protein encoded by GBA1) can be mis-trafficked to the lysosomal surface instead of the lysosomal lumen. There, it binds to and interferes with normal LAMP2A function, impeding processing of CMA client proteins, particularly alpha-synuclein.99”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [99]

    The passages under “Lysine to glutamine mutations mimic acetylation in aggregation experiments” and “The dual roles of lysine-based regulation of tau aggregation” concern tau fibril formation, not glucocerebrosidase trafficking or LAMP2A. Searches for GBA1, LAMP2A, chaperone-mediated autophagy, and alpha-synuclein found no passage in our copy addressing the attributed mechanism. No page numbers were provided for these passages. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Mutant glucocerebrosidase A (GBA1) can be mis-trafficked to the lysosomal surface instead of the lysosomal lumen.

    “Second, it was recently shown that mutant glucocerebrosidase A (the protein encoded by GBA1) can be mis-trafficked to the lysosomal surface instead of the lysosomal lumen. There, it binds to and interferes with normal LAMP2A function, impeding processing of CMA client proteins, particularly alpha-synuclein.99”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [99]

    The Discussion describes how lysine acetylation affects tau fibril formation, not glucocerebrosidase trafficking. Searches for GBA1, the lysosomal surface and lumen, LAMP2A, and chaperone-mediated autophagy found no passage addressing the attributed claim. Page numbers are not available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Almost 50% of proteins in the mammalian proteome feature a KFERQ-like motif, including TDP-43, alpha-synuclein, APP, and tau.

    “Almost 50% of the proteins in the mammalian proteome feature a KFERQ-like motif, including all the major aggregating proteins of neurodegenerative diseases (i.e., TDP-43, alpha-synuclein, APP, and tau).99,143–145”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [99]

    The Introduction (page unavailable) discusses tau’s amyloid-forming motifs and mentions chaperone-mediated autophagy, but does not identify a KFERQ-like motif. Searches for KFERQ, the proteome percentage, and the named proteins found no passage addressing the claim. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 70 · Cited by 25

Research works printed but not linked: 17

  1. [1]1. Vaquer-Alicea, J., Diamond, M. I. & Joachimiak, L. A. Tau strains shape disease. Acta Neuropathol. 1-15 (2021). doi:10.1007/s00401-021-02301-7 · DOI
  2. [4]4. Zhang, W. et al. Novel tau filament fold in corticobasal degeneration. Nature 580, 283287 (2020).
  3. [7]7. Kaufman, S. K. et al. Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron 1-17 (2016). doi:10.1016/j.neuron.2016.09.055 · DOI · Paper page
  4. [8]8. Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl. Acad. Sci. U.S.A. 110, 9535-9540 (2013).
  5. [11]11. Zwierzchowski-Zarate, A. N. et al. RNA induces unique tau strains and stabilizes Alzheimer's disease seeds. J. Biol. Chem. 298, 102132 (2022).
  6. [13]13. Mirbaha, H. et al. Inert and seed-competent tau monomers suggest structural origins of aggregation. eLife 7, 338 (2018).
  7. [16]16. Stelzl, L. S. et al. Global Structure of the Intrinsically Disordered Protein Tau Emerges from its Local Structure. bioRxiv 2021.11.23.469691 (2022). doi:10.1101/2021.11.23.469691 · DOI
  8. [17]17. Mirbaha, H. et al. Seed-competent tau monomer initiates pathology in a tauopathy mouse model. J. Biol. Chem. 102163 (2022). doi:10.1016/j.jbc.2022.102163 · DOI
  9. [22]22. Despres, C. et al. Identification of the Tau phosphorylation pattern that drives its aggregation. Proc. Natl. Acad. Sci. U.S.A. 114, 9080-9085 (2017).
  10. [35]35. Neumann-Staubitz, P., Lammers, M. & Neumann, H. Genetic Code Expansion Tools to Study Lysine Acylation. Adv Biol (Weinh) 5, e2100926 (2021).
  11. [42]42. Mullapudi, V. et al. Network of hotspot interactions cluster tau amyloid folds. bioRxiv 2022.07.01.498342 (2022). doi:10.1101/2022.07.01.498342 · DOI
  12. [45]45. Holmes, B. B. et al. Proteopathic tau seeding predicts tauopathy in vivo. doi:10.1073/pnas.1411649111 · DOI · Paper page
  13. [47]47. Hou, Z., Chen, D., Ryder, B. D. & Joachimiak, L. A. Biophysical properties of a tau seed. bioRxiv 2021.03.30.437772 (2021). doi:10.1101/2021.03.30.437772 · DOI
  14. [51]51. Rohou, A. & Grigorieff, N. CTFFIND4: Fast and accurate defocus estimation from electron micrographs. Journal of Structural Biology 192, 216-221 (2015).
  15. [52]52. Tang, G. et al. EMAN2: an extensible image processing suite for electron microscopy. Journal of Structural Biology 157, 38-46 (2007).
  16. [53]53. Wagner, T. et al. Two particle-picking procedures for filamentous proteins: SPHIREcrYOLO filament mode and SPHIRE-STRIPER. Acta Crystallogr D Struct Biol 76, 613620 (2020).
  17. [60]60. Fleishman, S. J. et al. RosettaScripts: a scripting language interface to the Rosetta macromolecular modeling suite. PLoS ONE 6, e20161 (2011).

Authors
Li, L., Nguyen, B. A., Mullapudi, V., Li, Y., Saelices, L., & Joachimiak, L. A.
Affiliations
The University of Texas Southwestern Medical Center (US)
ORCID
Venue
Structure
Publisher
Elsevier BV
Published
2023-09
Volume
31
Issue
9
Pages
1025-1037.e4
ISSN
0969-2126 (ISSN-L)
DOI
10.1016/j.str.2023.05.020
PMC
PMC10527703
OpenAlex
W4381481174
Cited by
25
References
70
Citations by year
2026: 6 · 2025: 13 · 2024: 4 · 2023: 2
FWCI
4.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Structure (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • NIH (1S10OD020103 01, 1S10OD021685-01A1)
  • CPRIT (RP170644)
  • Chan Zuckerberg Initiative (2018-191983)
  • Welch Foundation (I-1928-20200401)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
tau protein, lysine acetylation, tauopathy, tau aggregation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review