Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

Xiang, Xinyu; Arakhamia, Tamta; Carlomagno, Yari; Dhingra, Shikhar; Thierry, Manon; DeTure, Michael; Cook, Casey; Dickson, Dennis W.; Petrucelli, Leonard; Fitzpatrick, Anthony

doi:10.1101/2021.05.24.445353

Cited by 6 publications

(15 citation statements)

References 54 publications

(84 reference statements)

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“…Different tauopathies are associated with tau fibril inclusions with distinct isoform composition; for instance, AD and CTE are 3R + 4R tauopathies with all six isoforms present, PiD is characterized by 3R tau inclusions, and CBD, PSP, AGD, and GGT contain only 4R tau . Besides differences in the isoform composition, the cryo-EM structures of post-mortem brain-derived tau fibrils from AD, , PiD, CBD, , CTE, PSP, , AGD, and GGT confirm that a core segment of tau is precisely folded into distinct shapes in different diseases, and stacks in identical replicates into long fibrils.…”

Section: Tauopathy-specific Protein Folds In Tau Fibrilsmentioning

confidence: 86%

“…Within these two classes, tau fibrils differ on a substructure level; the AGD fold resembles the CBD fold but is slightly longer, and has a smaller nontau cavity between the R2 and C-terminal segment; the GGT fold is similar to the PSP fold in the three-layered arrangement but has a distinct chain turn and a different C-terminal packing direction. For several of these fibril structures, nonproteinous molecules have been suggested to be associated within the core of CTE, CBD, and PSP fibrils. Although the identity of these cofactor molecules is not known, their presence appears to be disease-specific.…”

Section: Tauopathy-specific Protein Folds In Tau Fibrilsmentioning

confidence: 99%

“…Schematics of the full-length tau and the fibril core constructs of four disease folds, − showing the major domains and location of the disease folds. The full-length tau here is the longest human tau isoform with 441 residues, containing N-terminus, proline-rich domain, microtubule biding repeats (MTBRs), and C-terminus.…”

Section: Tauopathy-specific Protein Folds In Tau Fibrilsmentioning

confidence: 99%

“…Given the distinct structural differences observed in different tauopathies, − structural biology tools with sufficiently high-resolution are needed to differentiate between the different disease phenotypic fibril shapes and to verify the seeded fibrils shapes. Ultrastructural and biochemical properties are often used as evidence for tau conformations, such as low-resolution morphology, , secondary structure, and proteolysis patterns. , Similar features between the seeded fibrils and the seeds are used as indications of tau templated seeding. − For example, Xu et al showed in a recent study that recombinant tau fibrils generated with AD-tau seeds is similar to AD-tau in terms of their ultrastructure, solubility, and conformation, as detected by conformation-dependent antibody DMR7 and MC1 that selectively bind to AD tau aggregates, indicating that AD-tau may have templated the aggregation of recombinant tau .…”

Section: Tracking Structural Evolution Of Tau In Seeded Aggregationmentioning

confidence: 99%

“…It was recently confirmed by cryogenic electron microscopy (cryo-EM) that tau protein adopts a variety of atomic structures (that we henceforth refer to as tau “shapes”) when incorporated in fibrils. The cryo-EM structures of post-mortem human brain-derived tau fibrils, thus far of Alzheimer’s disease (AD), , Pick’s disease (PiD), corticobasal degeneration (CBD), , chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), , argyrophilic grain disease (AGD), and globular glial tauopathy (GGT) reveal that a core segment of tau is precisely folded into a distinct shape, unique within each tauopathy disease category, that stacks in identical replicates into long (up to micrometer) fibrils.…”

Section: Introductionmentioning

confidence: 99%

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Illuminating the Structural Basis of Tau Aggregation by Intramolecular Distance Tracking: A Perspective on Methods

et al. 2022

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The aggregation of the tau protein is central to several neurodegenerative diseases, collectively known as tauopathies. High-resolution views of tau tangles accumulated under pathological conditions in post-mortem brains have been revealed recently by cryogenic electron microscopy. One of the striking discoveries was that fibril folds are unique to and homogeneous within one disease family, but typically different between different tauopathies. It is widely believed that seeded aggregation can achieve structural propagation of tau fibrils and generate pathological fibril structures. However, direct molecular level measurement of structural evolution during aggregation is missing. Here, we discuss our perspective on the biophysical approaches that can contribute to the ongoing debate regarding the prion-like propagation of tau and the role of cofactors. We discuss the unique potential of double electron–electron resonance (DEER)-based intramolecular distance measurement, sensitive to two to several nanometers distances. DEER can track the structural evolution of tau along the course of aggregation from the completely disordered state, to partially ordered and highly ordered fibril states, and has the potential to be a key tool to elucidate the disease-specific tau aggregation pathways.

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Section: Tauopathy-specific Protein Folds In Tau Fibrilsmentioning

confidence: 86%

Section: Tauopathy-specific Protein Folds In Tau Fibrilsmentioning

confidence: 99%

Section: Tauopathy-specific Protein Folds In Tau Fibrilsmentioning

confidence: 99%

Section: Tracking Structural Evolution Of Tau In Seeded Aggregationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Illuminating the Structural Basis of Tau Aggregation by Intramolecular Distance Tracking: A Perspective on Methods

et al. 2022

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Acetylation discriminates disease-specific tau deposition

Chakraborty,

Rivière,

Hebestreit

et al. 2023

Nat Commun

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Pathogenic aggregation of the protein tau is a hallmark of Alzheimer’s disease and several other tauopathies. Tauopathies are characterized by the deposition of specific tau isoforms as disease-related tau filament structures. The molecular processes that determine isoform-specific deposition of tau are however enigmatic. Here we show that acetylation of tau discriminates its isoform-specific aggregation. We reveal that acetylation strongly attenuates aggregation of four-repeat tau protein, but promotes amyloid formation of three-repeat tau. We further identify acetylation of lysine 298 as a hot spot for isoform-specific tau aggregation. Solid-state NMR spectroscopy demonstrates that amyloid fibrils formed by unmodified and acetylated three-repeat tau differ in structure indicating that site-specific acetylation modulates tau structure. The results implicate acetylation as a critical regulator that guides the selective aggregation of three-repeat tau and the development of tau isoform-specific neurodegenerative diseases.

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Mathematical topology and geometry-based classification of tauopathies

Sugiyama,

Kosik,

Panagiotou

2024

Sci Rep

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Neurodegenerative diseases, like Alzheimer’s, are associated with the presence of neurofibrillary lesions formed by tau protein filaments in the cerebral cortex. While it is known that different morphologies of tau filaments characterize different neurodegenerative diseases, there are few metrics of global and local structure complexity that enable to quantify their structural diversity rigorously. In this manuscript, we employ for the first time mathematical topology and geometry to classify neurodegenerative diseases by using cryo-electron microscopy structures of tau filaments that are available in the Protein Data Bank. By employing mathematical topology metrics (Gauss linking integral, writhe and second Vassiliev measure) we achieve a consistent, but more refined classification of tauopathies, than what was previously observed through visual inspection. Our results reveal a hierarchy of classification from global to local topology and geometry characteristics. In particular, we find that tauopathies can be classified with respect to the handedness of their global conformations and the handedness of the relative orientations of their repeats. Progressive supranuclear palsy is identified as an outlier, with a more complex structure than the rest, reflected by a small, but observable knotoid structure (a diagrammatic structure representing non-trivial topology). This topological characteristic can be attributed to a pattern in the beginning of the R3 repeat that is present in all tauopathies but at different extent. Moreover, by comparing single filament to paired filament structures within tauopathies we find a consistent change in the side-chain orientations with respect to the alpha carbon atoms at the area of interaction.

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Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

Cited by 6 publications

References 54 publications

Illuminating the Structural Basis of Tau Aggregation by Intramolecular Distance Tracking: A Perspective on Methods

Illuminating the Structural Basis of Tau Aggregation by Intramolecular Distance Tracking: A Perspective on Methods

Acetylation discriminates disease-specific tau deposition

Mathematical topology and geometry-based classification of tauopathies

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