Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG
Ontology highlight
ABSTRACT:
SUBMITTER: Peng Ge
PROVIDER: EMPIAR-11303 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description: Not available
| EMPIAR-11302 | biostudies-other
Project description: Not available
| EMPIAR-11301 | biostudies-other
Project description:Alzheimer's disease (AD) and many other neurodegenerative diseases are characterized by pathological aggregation of the protein tau. These tau aggregates spread in a stereotypical spatiotemporal pattern in the brain of each disease, suggesting that the misfolded tau can recruit soluble monomers to adopt the same pathological structure. To investigate whether recruited tau indeed adopts the same structure and properties as the original seed, here we template recombinant full-length 0N3R tau, 0N4R tau, and an equimolar mixture of the two using sarkosyl-insoluble tau extracted from AD brain and determine the structures of the resulting fibrils using cryoelectron microscopy. We show that these cell-free amplified tau fibrils adopt the same molecular structure as the AD paired-helical filament (PHF) tau but are unable to template additional monomers. Therefore, the PHF structure alone is insufficient for defining the pathological properties of AD tau, and other biochemical components such as tau posttranslational modifications, other proteins, polyanionic cofactors, and salt are required for the prion-like serial propagation of tauopathies.
| S-EPMC11440801 | biostudies-literature
Project description:Tau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimer's disease. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here, we report an elegant mechanism of Tau degradation involving the cochaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades Sarkosyl insoluble Tau and phosphorylated Tau. BAG2 levels in cells are under the physiological control of the microRNA miR-128a, which can tune paired helical filament Tau levels in neurons. Thus, we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.
| S-EPMC2768429 | biostudies-other
Project description:Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.
| S-EPMC10220082 | biostudies-literature
Project description:Post-translationally modified tau is the primary component of tau neurofibrillary tangles, a pathological hallmark of Alzheimer's disease and other tauopathies. Post-translational modifications (PTMs) within the tau microtubule (MT)-binding domain (MBD), which encompasses two hexapeptide motifs that act as critical nucleating regions for tau aggregation, can potentially modulate tau aggregation as well as interactions with MTs and membranes. Here, we characterize the effects of a recently discovered tau PTM, lysine succinylation, on tau-tubulin interactions and compare these to the effects of two previously reported MBD modifications, lysine acetylation and tyrosine phosphorylation. As generation of site-specific PTMs in proteins is challenging, we used short synthetic peptides to quantify the effects on tubulin binding of three site-specific PTMs located within the PHF6∗ (paired helical filament [PHF] residues 275-280) and PHF6 (residues 306-311) hexapeptide motifs: K280 acetylation, Y310 phosphorylation, and K311 succinylation. We compared these effects to those observed for MBD PTM-mimetic point mutations K280Q, Y310E, and K311E. Finally, we evaluated the effects of these PTM-mimetic mutations on MBD membrane binding and membrane-induced fibril and oligomer formation. We found that all three PTMs perturb tau MT binding, with Y310 phosphorylation exerting the strongest effect. PTM-mimetic mutations partially recapitulated the effects of the PTMs on MT binding and also disrupted tau membrane binding and membrane-induced oligomer and fibril formation. These results imply that these PTMs, including the novel and Alzheimer's disease-specific succinylation of tau K311, may influence both the physiological and pathological interactions of tau and thus represent targets for therapeutic intervention.
| S-EPMC8741514 | biostudies-literature
Project description: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. This provides a valuable tool with which to explore the effects of tau in cell culture. Here we have studied the cellular uptake of soluble oligomeric and fibrillar forms of dGAE and examined the downstream consequences of tau internalisation into differentiated SH-SY5Y neuroblastoma cells using fluorescence and electron microscopy alongside structural and biochemical analyses. The assembled dGAE shows more acute cytotoxicity than the soluble, non-aggregated form. Conversely, the soluble form is much more readily internalised and, once within the cell, is able to associate with endogenous tau resulting in increased phosphorylation and aggregation of endogenous tau, which accumulates in lysosomal/endosomal compartments. It appears that soluble oligomeric forms are able to propagate tau pathology without being acutely toxic. The model system we have developed now permits the molecular mechanisms of propagation of tau pathology to be studied in vitro in a more physiological manner with a view to development of novel therapeutic approaches.
| S-EPMC7427330 | biostudies-literature
Project description:Neurofibrillary pathology [paired helical filaments (PHFs)] formed by the microtubule-associated protein tau in a hyperphosphorylated form is a major hallmark of Alzheimer's disease and related disorders. The process of tau phosphorylation, thought to be of critical importance for PHF formation, and its potential link to neurodegeneration, however, is not understood very well, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. Here we describe the formation of highly phosphorylated tau, containing a number of PHF-like epitopes in torpor during hibernation. PHF-like phosphorylation of tau was not associated with fibril formation and was fully reversible after arousal. Distribution of PHF-like tau followed a consistent pattern, being most intense in the entorhinal cortex, hippocampus, and isocortical areas. Within the hippocampus, a particularly high labeling was seen in CA3 pyramidal cells. Somewhat lesser reactivity was present in CA1 neurons while dentate gyrus granule cells were not reactive. Formation of PHF-like tau in CA3 neurons was paralleled by the regression of synaptic contacts of the mossy fiber system terminating on CA3 apical dendrites. Mossy fiber afferentation was re-established during arousal, concomitantly with the decrease of PHF-like tau in CA3 neurons. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau. The repeated formation and degradation of PHF-like tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. Hibernation will, therefore, be a valuable model to study the regulation of PHF-like tau-phosphorylation and its cell biological sequelae under physiological in vivo conditions.
| S-EPMC6740664 | biostudies-literature
Project description:Tau is a neuronal phosphoprotein the expression of which is developmentally regulated. A single tau isoform is expressed in fetal human brain but six isoforms are expressed in adult human brain, with the fetal isoform corresponding to the shortest adult isoform. Phosphorylation is also developmentally regulated, as fetal tau is phosphorylated at more sites than adult tau. In Alzheimer's disease, the six adult tau isoforms become hyperphosphorylated and form the paired helical filament (PHF), the major fibrous component of the neurofibrillary lesions. One way to identify phosphorylated sites in tau is to use antibodies that recognize phosphorylated residues within a specific amino acid sequence. We here characterize the two novel phosphorylation-dependent anti-tau antibodies AT270 and AT180 and identify their epitopes as containing phosphorylated Thr-181 and Thr-231 respectively. With these antibodies we show that these two threonine residues are partially phosphorylated in fetal and adult tau and almost fully phosphorylated in PHF tau. This result contrasts with previous studies of Ser-202 and Ser-396 which are partially phosphorylated in fetal tau, unphosphorylated in adult tau but almost fully phosphorylated in PHF tau.
| S-EPMC1137067 | biostudies-other
Project description: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. The ability of tau to adopt a wide variety of conformations appears fundamental both to its biological function and also its association with neurodegenerative diseases. The recently highlighted involvement of low-complexity domains in liquid-liquid phase separation provides a critical link between the soluble function and the insoluble dysfunctional properties of tau.
| S-EPMC9760425 | biostudies-literature