Variations in filament conformation dictate seeding barrier between three- and four-repeat Tau

Dinkel, Paul D.; Siddiqua, Ayisha; Huynh, Huy; Shah, Monil; Margittai, Martin

doi:10.1021/bi2004685

Cited by 104Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

Variations in filament conformation dictate seeding barrier between three- and four-repeat Tau

Dinkel, Paul D., Siddiqua, Ayisha, Huynh, Huy, Shah, Monil, Margittai, Martin·2011·Biochemistry

DOI 10.1021/bi2004685

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Abstract

Tau filaments are the pathological hallmark of >20 neurodegenerative diseases including Alzheimer's disease. Six tau isoforms exist that can be grouped into 4-repeat (4R) tau and 3-repeat (3R) tau based on the presence or absence of the second of four microtubule binding repeats. Recent evidence suggests that tau filaments can transfer between cells and spread through the brain. Here we demonstrate in vitro that seeded filament growth, a prerequisite for tau spreading, is crucially dependent on the isoform composition of individual seeds. Seeds of 3R tau and 3R/4R tau recruit both types of isoforms. Seeds of 4R tau recruit 4R tau, but not 3R tau, establishing an asymmetric barrier. Conformational templating of 4R tau onto 3R tau seeds eliminates this barrier, giving rise to a new type of tau filament. These findings provide fundamental mechanistic insights into the seeding, propagation, and diversification of tau filaments.

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Biotinylated K19 was unable to capture fibrils.
“Notably, biotinylated K19 was unable to capture fibrils (Fig. 4B), consistent with the observation that K19 does not grow onto K18 seeds (42).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [42]

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Peer Review #3 of "Concentration-dependent polymorphism of insulin amyloid fibrils (v0.1)"
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Additional file 1 of Tau seed amplification assay reveals relationship between seeding and pathological forms of tau in Alzheimer’s disease brain
Frey, B., Holzinger, D., Taylor, K. C., Ehrnhoefer, D. E., Striebinger, A., Biesinger, S., Gasparini, L., O’Neill, M. J., Wegner, F., Barghorn, S., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26639710
Additional file 1 of Tau seeding activity in various regions of down syndrome brain assessed by two novel assays
Jin, N., 顾建兰, Wu, R., Chu, D., Tung, Y. C., Węgiel, J., Wisniewski, T., Gong, C.-X., Iqbal, K., & Liu, F. (2022) · Figshare · doi:10.6084/m9.figshare.20968215
Étude de l’agrégation des protéines intrinsèquement désordonnées impliquées dans les maladies d’Alzheimer et de Parkinson
Lopez, J. M. (2015) · theses.fr (ABES) · doi:10.70675/0f47a19bz2dbez40a1zac55z083f0c564180

Structural Polymorphism in Tau Filaments: An Implication for Neurodegenerative Diseases
Siddiqua, A. (2012) · Digital Commons - DU (University of Denver)
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Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau
Siddiqua, A., Luo, Y., Meyer, V., Swanson, M. A., Yu, X., Wei, G., Zheng, J., Eaton, G. R., Ma, B., Nussinov, R., et al. (2012) · Journal of the American Chemical Society · doi:10.1021/ja303498q · Cited by 75 · see citing works
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Three- and Four-repeat Tau Coassemble into Heterogeneous Filaments
Siddiqua, A., & Margittai, M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.185728 · Cited by 65 · see citing works
Self-citation
Mechanistic Insight into Tau Fibril Cross-Seeding Barriers: Structural Order and Disorder
Weismiller, H. A. (2019) · Digital Commons - DU (University of Denver)
Seeded propagation of Tau fibrils
Dinkel, P. D. (2013) · Digital Commons - DU (University of Denver)
Self-citation

Authors: Dinkel, P. D., Siddiqua, A., Huynh, H., Shah, M., & Margittai, M.
Affiliations: University of Denver (US)
Corresponding author: Margittai, Martin
ORCID: Siddiqua, Ayisha
Margittai, Martin
Venue: Biochemistry
Publisher: American Chemical Society (ACS)
Published: 2011-05-02
Volume: 50
Issue: 20
Pages: 4330-4336
ISSN: 0006-2960 (ISSN-L)
1520-4995
DOI: 10.1021/bi2004685
OpenAlex: W2330831003
Cited by: 104
References: 47
Citations by year: 2026: 1 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 14 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 10 · 2014: 8 · 2013: 9 · 2012: 5
FWCI: 5.23
Type: journal article
Language: en
Open access: closed
Locations: Biochemistry (publishedVersion)
PubMed (publishedVersion)
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
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: tau protein, tau isoforms, 4-repeat tau, tau propagation, Alzheimer's disease, microtubule-binding repeats
MeSH terms: tau Proteins, Repetitive Sequences, Amino Acid, Protein Structure, Quaternary, Protein Multimerization

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Variations in filament conformation dictate seeding barrier between three- and four-repeat Tau

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