Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Filamentous Aggregates of Tau Proteins Fulfil Standard Amyloid Criteria Provided by the Fuzzy Oil Drop (FOD) Model.

ABSTRACT: Abnormal filamentous aggregates that are formed by tangled tau protein turn out to be classic amyloid fibrils, meeting all the criteria defined under the fuzzy oil drop model in the context of amyloid characterization. The model recognizes amyloids as linear structures where local hydrophobicity minima and maxima propagate in an alternating manner along the fibril's long axis. This distribution of hydrophobicity differs greatly from the classic monocentric hydrophobic core observed in globular proteins. Rather than becoming a globule, the amyloid instead forms a ribbonlike (or cylindrical) structure.

SUBMITTER: Dulak D

PROVIDER: S-EPMC6213535 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Filamentous Aggregates of Tau Proteins Fulfil Standard Amyloid Criteria Provided by the Fuzzy Oil Drop (FOD) Model.

Dułak Dawid D Gadzała Małgorzata M Banach Mateusz M Ptak Magdalena M Wiśniowski Zdzisław Z Konieczny Leszek L Roterman Irena I

International journal of molecular sciences 20180925 10

Abnormal filamentous aggregates that are formed by tangled tau protein turn out to be classic amyloid fibrils, meeting all the criteria defined under the fuzzy oil drop model in the context of amyloid characterization. The model recognizes amyloids as linear structures where local hydrophobicity minima and maxima propagate in an alternating manner along the fibril's long axis. This distribution of hydrophobicity differs greatly from the classic monocentric hydrophobic core observed in globular p ...[more]

PMID: 30257460

Similar Datasets

"Fuzzy oil drop" model verified positively.

Project description:The "fuzzy oil drop" model assuming the structure of the hydrophobic core of the form of 3-D Gauss function appeared to be verified positively. The protein 1NMF belonging to downhill proteins was found to represent the hydrophobic density distribution accordant with the assumed model. The accordance of the protein structure with the assumed model was measured using elements of theory information. This observation opens the possibility to simulate the folding process as influenced by external force field of hydrophobic character.

| S-EPMC3044424 | biostudies-other

Structural Characterization of Tau in Fuzzy Tau:Tubulin Complexes.

Project description:Tau is a neuronal microtubule (MT)-associated protein of significant interest due to its association with several neurodegenerative disorders. Tau's intrinsic disorder and the dynamic nature of its interactions with tubulin and MTs make its structural characterization challenging. Here, we use an environmentally sensitive fluorophore as a site-specific probe of tau bound to soluble tubulin. Comparison of our results with a recently published tau:MT cryoelectron microscopy model reveals structural similarities between tubulin- and MT-bound tau. Analysis of residues across the repeat regions reveals a hierarchy in tubulin occupancy, which may be relevant to tau's ability to differentiate between tubulin and MTs. As binding to soluble tubulin is a critical first step in MT polymerization, our characterization of the structural features of tau in dynamic, fuzzy tau:tubulin assemblies advances our understanding of how tau functions in the cell and how function may be disrupted in disease.

| S-EPMC7176406 | biostudies-literature

Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme.

Project description:Filamentous aggregates (fibrils) are regarded as the final stage in the assembly of amyloidogenic proteins and are formed in many neurodegenerative diseases. Accumulation of aggregates occurs as a result of an imbalance between their formation and removal. Here we use single-aggregate imaging to show that large fibrils assembled from full-length tau are substrates of the 26S proteasome holoenzyme, which fragments them into small aggregates. Interestingly, although degradation of monomeric tau is not inhibited by adenosine 5'-(3-thiotriphosphate) (ATPγS), fibril fragmentation is predominantly dependent on the ATPase activity of the proteasome. The proteasome holoenzyme also targets fibrils assembled from α-synuclein, suggesting that its fibril-fragmenting function may be a general mechanism. The fragmented species produced by the proteasome shows significant toxicity to human cell lines compared with intact fibrils. Together, our results indicate that the proteasome holoenzyme possesses a fragmentation function that disassembles large fibrils into smaller and more cytotoxic species.

| S-EPMC6381791 | biostudies-literature

Prediction of functional sites based on the fuzzy oil drop model.

Project description:A description of many biological processes requires knowledge of the 3-D structure of proteins and, in particular, the defined active site responsible for biological function. Many proteins, the genes of which have been identified as the result of human genome sequencing, and which were synthesized experimentally, await identification of their biological activity. Currently used methods do not always yield satisfactory results, and new algorithms need to be developed to recognize the localization of active sites in proteins. This paper describes a computational model that can be used to identify potential areas that are able to interact with other molecules (ligands, substrates, inhibitors, etc.). The model for active site recognition is based on the analysis of hydrophobicity distribution in protein molecules. It is shown, based on the analyses of proteins with known biological activity and of proteins of unknown function, that the region of significantly irregular hydrophobicity distribution in proteins appears to be function related.

| S-EPMC1876487 | biostudies-literature

Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro.

Project description:The aggregation of the microtubule-associated protein tau is a seminal event in many neurodegenerative diseases, including Alzheimer's disease. The inhibition or reversal of tau aggregation is therefore a potential therapeutic strategy for these diseases. Fungal natural products have proven to be a rich source of useful compounds having wide varieties of biological activities. We have previously screened Aspergillus nidulans secondary metabolites for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol. One aggregation inhibitor identified was asperbenzaldehyde, an intermediate in azaphilone biosynthesis. We therefore tested 11 azaphilone derivatives to determine their tau assembly inhibition properties in vitro. All compounds tested inhibited tau filament assembly to some extent, and four of the 11 compounds had the advantageous property of disassembling preformed tau aggregates in a dose-dependent fashion. The addition of these compounds to the tau aggregates reduced both the total length and number of tau polymers. The most potent compounds were tested in in vitro reactions to determine whether they interfere with tau's normal function of stabilizing microtubules (MTs). We found that they did not completely inhibit MT assembly in the presence of tau. These derivatives are very promising lead compounds for tau aggregation inhibitors and, more excitingly, for compounds that can disassemble pre-existing tau filaments. They also represent a new class of anti-tau aggregation compounds with a novel structural scaffold.

| S-EPMC5112770 | biostudies-literature

Comparing Combination Drop Therapy to a Standard Drop Regimen After Routine Cataract Surgery.

Project description:PurposeTo evaluate the efficacy of a combined steroid/antibiotic/non-steroidal anti-inflammatory drop relative to a regimen of multiple drops after cataract surgery.SettingSingle clinical practice in the USA.DesignProspective randomized contralateral eye study.MethodsSubjects presenting for bilateral cataract surgery were enrolled with contralateral eyes randomly assigned to one of the two groups. Test eyes received a combination therapy (prednisolone acetate 1%, gatifloxacin 0.5%, and bromfenac sodium 0.075%) while control eyes received the same medications in separate drops (bromfenac sodium was 0.07%). Subjects were examined 1, 15 and 30 days after surgery. Visual acuities were measured, along with the refraction, intraocular pressure, patient pain and satisfaction, macular thickness and corneal pachymetry. The primary measure of interest was the change in macular thickness from baseline to the 15- and 30-day visits. The frequency and severity of reported ocular adverse events were tabulated for each group and compared.ResultsThirty-three subjects completed the study. Changes in central macular thickness were similar between groups, with only one control eye exhibiting significant macular edema. No differences in visual acuity, corneal edema, cells or flare were observed between groups. There were eight mild adverse events reported for all eyes of all subjects; the difference in the number of eyes experiencing adverse events was not statistically significantly different between groups (p ≥ 0.05 for all comparisons). While subjective symptoms were similar, all subjects indicated that they preferred the combination drop.ConclusionA combination drop showed similar efficacy to multiple drops and was overwhelmingly preferred by subjects.

| S-EPMC7360419 | biostudies-literature

?-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates.

Project description:Multiple G protein-coupled receptors (GPCRs) are targets in the treatment of dementia, and the arrestins are common to their signaling. ?-Arrestin2 was significantly increased in brains of patients with frontotemporal lobar degeneration (FTLD-tau), a disease second to Alzheimer's as a cause of dementia. Genetic loss and overexpression experiments using genetically encoded reporters and defined mutant constructs in vitro, and in cell lines, primary neurons, and tau P301S mice crossed with ?-arrestin2-/- mice, show that ?-arrestin2 stabilizes pathogenic tau and promotes tau aggregation. Cell and mouse models of FTLD showed this to be maladaptive, fueling a positive feedback cycle of enhanced neuronal tau via non-GPCR mechanisms. Genetic ablation of ?-arrestin2 markedly ablates tau pathology and rescues synaptic plasticity defects in tau P301S transgenic mice. Atomic force microscopy and cellular studies revealed that oligomerized, but not monomeric, ?-arrestin2 increases tau by inhibiting self-interaction of the autophagy cargo receptor p62/SQSTM1, impeding p62 autophagy flux. Hence, reduction of oligomerized ?-arrestin2 with virus encoding ?-arrestin2 mutants acting as dominant-negatives markedly reduces tau-laden neurofibrillary tangles in FTLD mice in vivo. Reducing ?-arrestin2 oligomeric status represents a new strategy to alleviate tau pathology in FTLD and related tauopathies.

| S-EPMC7060747 | biostudies-literature

Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates.

Project description:Tau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far, visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single-molecule localization microscopy, we show that tau forms small oligomers on microtubules ex vivo. These oligomers are distinct from those found in cells exhibiting tau aggregation and could be precursors of aggregated tau in pathology. Furthermore, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates tau's nanoscale composition under nonaggregated and aggregated conditions ex vivo.

| S-EPMC8126857 | biostudies-literature

PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding.

Project description:Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders characterized by the deposition of hyperphosphorylated tau aggregates. Proteopathic tau seeds spread through the brain in a temporospatial pattern, indicative of transsynaptic propagation. It is hypothesized that reducing the uptake of tau seeds and subsequent induction of tau aggregation could be a potential approach for abrogating disease progression in AD. Here, we studied to what extent different endosomal routes play a role in the neuronal uptake of preformed tau seeds. Using pharmacological and genetic tools, we identified dynamin-1, actin, and Rac1 as key players. Furthermore, inhibition of PIKfyve, a protein downstream of Rac1, reduced both the trafficking of tau seeds into lysosomes and the induction of tau aggregation. Our work shows that tau aggregates are internalized by a specific endocytic mechanism and that their fate once internalized can be pharmacologically modulated to reduce tau seeding in neurons.

| S-EPMC8134070 | biostudies-literature

Network analysis reveals strain-dependent response to misfolded tau aggregates

Project description:To investigate the effect of wild-derived genetic background on modeling tau aggregation, we injected either AAV-eGFP or AAV-hTauP301L into postnatal day 0 mice to drive widespread expression. We then performed gene expression profiling analysis using data obtained from mRNA-seq from mouse brain cortex of 6 month old hTauP301L- or eGFP-mice.

2023-07-25 | GSE223840 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data