Structural disorder in four-repeat Tau fibrils reveals a new mechanism for barriers to cross-seeding of Tau isoforms
Open accessAbstract
The intracellular deposition of fibrils composed of the microtubule-associated protein Tau is a characteristic feature of Alzheimer's disease (AD) and other fatal neurodegenerative disorders collectively known as tauopathies. Short Tau fibrils spread intracerebrally through transfer between interconnected neurons. Once taken up by a recipient cell, Tau fibrils recruit Tau monomers onto their ends. Based on the number of microtubule-binding repeats, there are two distinct groups of Tau isoforms: three-repeat (3R) Tau and four-repeat (4R) Tau. In AD, all Tau isoforms are deposited, whereas in other tauopathies, only 3R or 4R Tau isoforms are deposited. The molecular basis for these isoform-specific depositions is poorly understood, although conformation-based cross-seeding barriers are key. Here, we used sedimentation assays, EPR spectroscopy, and other structural readouts to better understand the cross-seeding barriers of 4R Tau fibrils. We observed that fibrils formed from truncated Tau (K18), but not full-length Tau (htau40), exhibit a barrier that inhibits 3R Tau recruitment. Investigating an array of differently sized fragments, we found that the Tau C terminus modulates the cross-seeding barrier and that the N terminus plays a synergistic role. Two disease-associated Tau variants, P301S and P301L, also established strong cross-seeding barriers. EPR analysis indicated that fibrils seeded with truncated and mutated Tau, but not htau40, are structurally disordered in the second half of repeat four and onward. These findings suggest that the disorder in this region diminishes the ability of 4R Tau fibrils to recruit 3R Tau monomers, revealing a new mechanism for Tau cross-seeding barriers.
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The fibrils employed in the current study are known to have different folds.
“The fibrils that were employed in the current study are known to have different folds.”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [51]
The section “Pro-301 mutants and htau40 form distinct clouds of fibril conformers” reports that htau40 fibrils differ structurally from P301S- and P301L-seeded fibrils. It also says that all three types form clouds of conformers and that insight into their particular structures is limited, so it does not establish distinct, defined folds for the fibrils described in the citing sentence. (LLM, conf=0.81)
Experimental — accuracy not yet measuredFibrils formed in the presence of heparin are heterogeneous ensembles.
“fibrils formed in the presence of heparin are heterogeneous ensembles (51, 52)”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [51]
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RT-QuIC detection of tauopathies using full-length tau substrates
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Self-citation
- Authors
- Weismiller, H. A., Murphy, R., Wei, G., Ma, B., Nussinov, R., & Margittai, M.
- Affiliations
- University of Denver (US)
- Fudan University (CN)
- National Institutes of Health (US)
- Corresponding author
- Margittai, Martin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 293
- Issue
- 45
- Pages
- 17336-17348
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6231118
- OpenAlex
- W2892916393
- Cited by
- 44
- References
- 8
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 3 · 2023: 7 · 2022: 2 · 2021: 10 · 2020: 4 · 2019: 13
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons - DU (University of Denver) (submittedVersion)
- Funders
- HHS | National Institutes of Health (NIH) (R21AG051833, HHSN261200800001E)
- National Natural Science Foundation of China (NSFC) (11674065)
- 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 fibrils, cross-seeding, tau isoforms, 3R tau, 4R tau, structural disorder, Alzheimer's disease, tauopathy, truncated tau, K18, C-terminal domain, N-terminal domain, fibril conformation, protein aggregation
- MeSH terms
- Protein Domains, Alzheimer Disease, Amino Acid Sequence, Humans, tau Proteins, Sequence Deletion, Protein Isoforms, Multiprotein Complexes
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