ArticleThe Journal of biological chemistry2018
Structural disorder in four-repeat Tau fibrils reveals a new mechanism for barriers to cross-seeding of Tau isoforms.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- The lifespan continuum of brain disorders: investigating links between neurodevelopmental and neurodegenerative disease-chicken or egg?Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Making tau amyloid models in vitro: a crucial and underestimated challenge.FEBS letters · 2025Review
- Cellular Uptake of Tau Aggregates Triggers Disulfide Bond Formation in Four-Repeat Tau Monomers.ACS chemical neuroscience · 2025Article
- The Role of Tau Pathology in Alzheimer's Disease and Down Syndrome.Journal of clinical medicine · 2024Review
- Article
- Review
- MAP2 caps tau fibrils and inhibits aggregation.The Journal of biological chemistry · 2023Article
- The propagation mechanisms of extracellular tau in Alzheimer's disease.Journal of neurology · 2022Review
- The prion-like transmission of tau oligomersFrontiers in aging neuroscience · 2022Review
- A thiol-based intramolecular redox switch in four-repeat tau controls fibril assembly and disassembly.The Journal of biological chemistry · 2021Article
- Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain.Journal of clinical medicine · 2021Article
- Misfolding and Self-Assembly Dynamics of Microtubule-Binding Repeats of the Alzheimer-Related Protein Tau.Journal of chemical information and modeling · 2021Article
- The AD tau core spontaneously self-assembles and recruits full-length tau to filaments.Cell reports · 2021Article
- Effect of spin labelling on the aggregation kinetics of yeast prion protein Ure2.Royal Society open science · 2021Article
- Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.Chemical reviews · 2021Review
- Article
- Regulatory mechanisms of tau protein fibrillation under the conditions of liquid-liquid phase separation.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Solid-state NMR investigation of the involvement of the P2 region in tau amyloid fibrils.Scientific reports · 2020Article
- Article
- Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples.The Journal of biological chemistry · 2019Article
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6 authors.
Funding
Abstract
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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