Corrigendum: The disease associated Tau35 fragment has an increased propensity to aggregate compared to full-length tau.

[This corrects the article DOI: 10.3389/fmolb.2021.

Dityrosine cross-linking and its potential roles in Alzheimer's disease.

Oxidative stress is a significant source of damage that accumulates during aging and contributes to Alzheimer's disease (AD) pathogenesis. Oxidation of proteins can give rise to covalent links between adjacent tyrosines known as dityrosine (DiY) cross-linking, amongst other modifications, and this observation suggests that DiY could serve as a biomarker of accumulated oxidative stress over the lifespan. Many studies have focused on understanding the contribution of DiY to AD pathogenesis and have revealed that DiY crosslinks can be found in both Aβ and tau deposits - the two key proteins involved in the formation of amyloid plaques and tau tangles, respectively.

Fluorine-based Zn salan complexes.

We synthesised and characterised the racemic and chiral versions of two Zn salan fluorine-based complexes from commercially available materials. The complexes are susceptible to absorbing HO from the atmosphere. In solution (DMSO-HO) and at the millimolar level, experimental and theoretical studies identify that these complexes exist in a dimeric-monomeric equilibrium.

Chiral CoY Propeller-Shaped Chemosensory Platforms Based on F-NMR.

Two propeller-shaped chiral CoY complexes built from fluorinated ligands are synthesized and characterized by single-crystal X-ray diffraction (SXRD), IR, UV-vis, circular dichroism (CD), elemental analysis, thermogravimetric analysis (TGA), electron spray ionization mass spectroscopy (ESI-MS), and NMR (H, C, and F). This work explores the sensing and discrimination abilities of these complexes, thus providing an innovative sensing method using a F NMR chemosensory system and opening new directions in 3d/4f chemistry. Control experiments and theoretical studies shed light on the sensing mechanism, while the scope and limitations of this method are discussed and presented.

Solid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391).

Aggregation of the tau protein into fibrillar cross-β aggregates is a hallmark of Alzheimer's diseases (AD) and many other neurodegenerative tauopathies. Recently, several core structures of patient-derived tau paired helical filaments (PHFs) have been solved revealing a structural variability that often correlates with a specific tauopathy. To further characterize the dynamics of these fibril cores, to screen for strain-specific small molecules as potential biomarkers and therapeutics, and to develop strain-specific antibodies, recombinant in-vitro models of tau filaments are needed.

Shapeshifting tau: from intrinsically disordered to paired-helical filaments.

Tau is an intrinsically disordered protein that has the ability to self-assemble to form paired helical and straight filaments in Alzheimer's disease, as well as the ability to form additional distinct tau filaments in other tauopathies. In the presence of microtubules, tau forms an elongated form associated with tubulin dimers via a series of imperfect repeats known as the microtubule binding repeats. Tau has recently been identified to have the ability to phase separate in vitro and in cells.

An Additive-Free Model for Tau Self-Assembly.

Tau is a natively unfolded protein that contributes to the stability of microtubules. Under pathological conditions such as Alzheimer's disease (AD), tau protein misfolds and self-assembles to form paired helical filaments (PHFs) and straight filaments (SFs). Full-length tau protein assembles poorly and its self-assembly is enhanced with polyanions such as heparin and RNA in vitro, but a role for heparin or other polyanions in vivo remains unclear.

Charge screening wormlike micelles affects extensional relaxation time and noodle formation.

A functionalised dipeptide that self-assembles to form wormlike micelles at high pH can be treated as a surfactant. By varying salt concentration, the self-assembled structures and interactions between them change, resulting in solutions with very different shear and extensional viscosity. From these, gel noodles with different mechanical properties can be prepared.

Dityrosine Cross-links are Present in Alzheimer's Disease-derived Tau Oligomers and Paired Helical Filaments (PHF) which Promotes the Stability of the PHF-core Tau (297-391) In Vitro.

A characteristic hallmark of Alzheimer's Disease (AD) is the pathological aggregation and deposition of tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs). Oxidative stress is an early event during AD pathogenesis and is associated with tau-mediated AD pathology. Oxidative environments can result in the formation of covalent dityrosine crosslinks that can increase protein stability and insolubility.

Structural Identification of Individual Helical Amyloid Filaments by Integration of Cryo-Electron Microscopy-Derived Maps in Comparative Morphometric Atomic Force Microscopy Image Analysis.

The presence of amyloid fibrils is a hallmark of more than 50 human disorders, including neurodegenerative diseases and systemic amyloidoses. A key unresolved challenge in understanding the involvement of amyloid in disease is to explain the relationship between individual structural polymorphs of amyloid fibrils, in potentially mixed populations, and the specific pathologies with which they are associated. Although cryo-electron microscopy (cryo-EM) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy methods have been successfully employed in recent years to determine the structures of amyloid fibrils with high resolution detail, they rely on ensemble averaging of fibril structures in the entire sample or significant subpopulations.

The Disease Associated Tau35 Fragment has an Increased Propensity to Aggregate Compared to Full-Length Tau.

Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Tau35 may have structural properties distinct from those of other tau species that could account for its pathological role in disease.

Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297-391) Intermediates.

The self-assembly of tau into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs) is a significant event in Alzheimer's disease (AD) pathogenesis. Numerous post-translational modifications enhance or inhibit tau assembly into NFTs. Oxidative stress, which accompanies AD, induces multiple post-translational modifications in proteins, including the formation of dityrosine (DiY) cross-links.

Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target.

Tau plays an important pathological role in a group of neurodegenerative diseases called tauopathies, including Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy and corticobasal degeneration. In each disease, tau self-assembles abnormally to form filaments that deposit in the brain. Tau is a natively unfolded protein that can adopt distinct structures in different pathological disorders.

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity.

Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-β (Aβ) forms DiY and DiY-cross-linked Aβ is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of Aβ42 results in an increase in DiY cross-links.

Paired Helical Filament-Forming Region of Tau (297-391) Influences Endogenous Tau Protein and Accumulates in Acidic Compartments in Human Neuronal Cells.

Assembly of tau protein into paired helical filaments and straight filaments is a key feature of Alzheimer's disease. Aggregation of tau has been implicated in neurodegeneration, cellular toxicity and the propagation, which accompanies disease progression. We have reported previously that a region of tau (297-391), referred to as dGAE, assembles spontaneously in physiological conditions to form paired helical filament-like fibres in vitro in the absence of additives such as heparin.

Tau (297-391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer's disease brain.

The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer's disease (AD) and other tauopathies. Full-length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297-391 known as 'dGAE', spontaneously forms cross-β-containing PHFs and straight filaments under physiological conditions.

Using chirality to influence supramolecular gelation.

Most low molecular weight gelators are chiral, with racemic mixtures often unable to form gels. Here, we show an example where all enantiomers, diastereomers and racemates of a single functionalized dipeptide can form gels. At high pH, different self-assembled aggregates are formed and these directly template the structures formed in the gel.

Zinc-dysprosium functionalized amyloid fibrils.

The heterometallic Zn2Dy2 entity bearing partially saturated metal centres covalently decorates a highly ordered amyloid fibril core and the functionalised assembly exhibits catalytic Lewis acid behaviour.

The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

Insights into tau molecular structures have advanced significantly in recent years. This field has been the subject of recent breakthroughs, including the first cryo-electron microscopy structures of tau filaments from Alzheimer's and Pick's disease inclusions, as well as the structure of the repeat regions of tau bound to microtubules. Tau structure covers various species as the tau protein itself takes many forms.

The CDR1 and Other Regions of Immunoglobulin Light Chains are Hot Spots for Amyloid Aggregation.

Immunoglobulin light chain-derived (AL) amyloidosis is a debilitating disease without known cure. Almost nothing is known about the structural factors driving the amyloidogenesis of the light chains. This study aimed to identify the fibrillogenic hotspots of the model protein 6aJL2 and in pursuing this goal, two complementary approaches were applied.

Methods for Structural Analysis of Amyloid Fibrils in Misfolding Diseases.

Many proteins and peptides are able to self-assemble in solution in vitro and in vivo to form amyloid-like fibrils. These fibrils share common structural characteristics. In order for a fibril to be characterized as amyloid, it is expected to fit certain criteria including the composition of cross-β.

Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT).

Alzheimer's disease is a tauopathy characterized by pathological fibrillization of tau protein to form the paired helical filaments (PHFs), which constitute neurofibrillary tangles. The methylthioninium (MT) moiety reverses the proteolytic stability of the PHF core and is in clinical development for treatment of Alzheimer's disease in a stable reduced form as leuco-MT. It has been hypothesized that MT acts via oxidation of cysteine residues, which is incompatible with activity in the predominantly reducing environment of living cells.

Alzheimer's Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking.

Alzheimer's disease is characterized by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood.

The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson's disease.

Parkinson's disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable α-synuclein (α-syn) amyloid fibrils. α-synuclein is an intrinsically disordered protein that has the capacity to assemble to form β-sheet rich fibrils. Oxidiative stress and metal rich environments have been implicated in triggering assembly.