Network analysis reveals strain-dependent response to misfolded tau aggregates
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE223840 | GEO | 2023/07/25
REPOSITORIES: GEO
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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 Nanostring nCounter Mouse Neuroinflammation Panel from mouse brain cortex of 6 month old hTauP301L- or eGFP-mice.
2023-07-25 | GSE233988 | GEO
Project description:Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple Tauopathies and precedes neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we find that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in Tauopathies.
2023-05-17 | GSE226624 | GEO
Project description:We report the isolation and sequencing of tau aggregates from [1] HEK293 cells expressing Tau-RD-P301S-CFP/YFP that have been seeded with preformed fibrils from the brain of P301S mice (B6-Tg(Thy1-MAPT*P301S)2541; referred to as Tg2541 mice). Tau aggregates were isolated by differential centrifugation followed by fluorescence automated particle sorting using a BD FACSaraia. We found that these tau aggregates were enriched for particular small non-coding RNAs, including snoRNAs and snRNAs. [2] the following mice: FvBB6F1-Tg(Camk2a-tTa),(tetO-MAPT*wt)21221 (referred to as rTg21221 or WT tau mice in the paper) and FvBB6F1-Tg(Camk2a-tTA)1Mmay, (tet)-tdTomato-Syp/EGFP)1.1Luo/J,(tetO-MAPT*P301L)4510 (referred to as rTg4510 or P301L mice in the paper). Briefly, tau aggregates were isolated by 1% sarkosyl extraction (to enrich for insoluble proteins) followed by immunoprecipitation of tau using the tau-12 antibody (see Methods section of associated paper for further details). We found that these tau aggregates were enriched for particular small non-coding RNAs, including snRNAs and some snoRNAs. [3] Sequencing of HEK293 tau biosensor cells with and without tau aggregates reveals evidence of significant splicing alterations. Specifically we observed an increase in intron retention events in cells that contain tau aggregates relative to cells without tau aggregates.
2021-04-06 | GSE148716 | GEO
Project description:Yuraszeck2010 - Vulnerabilities in the Tau
Network in Tau Pathophysiology
This model is described in the article:
Vulnerabilities in the tau
network and the role of ultrasensitive points in tau
pathophysiology.
Yuraszeck TM, Neveu P,
Rodriguez-Fernandez M, Robinson A, Kosik KS, Doyle FJ 3rd.
PLoS Comput. Biol. 2010; 6(11):
e1000997
Abstract:
The multifactorial nature of disease motivates the use of
systems-level analyses to understand their pathology. We used a
systems biology approach to study tau aggregation, one of the
hallmark features of Alzheimer's disease. A mathematical model
was constructed to capture the current state of knowledge
concerning tau's behavior and interactions in cells. The model
was implemented in silico in the form of ordinary differential
equations. The identifiability of the model was assessed and
parameters were estimated to generate two cellular states: a
population of solutions that corresponds to normal tau
homeostasis and a population of solutions that displays
aggregation-prone behavior. The model of normal tau homeostasis
was robust to perturbations, and disturbances in multiple
processes were required to achieve an aggregation-prone state.
The aggregation-prone state was ultrasensitive to perturbations
in diverse subsets of networks. Tau aggregation requires that
multiple cellular parameters are set coordinately to a set of
values that drive pathological assembly of tau. This model
provides a foundation on which to build and increase our
understanding of the series of events that lead to tau
aggregation and may ultimately be used to identify critical
intervention points that can direct the cell away from tau
aggregation to aid in the treatment of tau-mediated (or
related) aggregation diseases including Alzheimer's.
This model is hosted on
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and identified by:
BIOMD0000000542.
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To the extent possible under law, all copyright and related or
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2024-09-02 | BIOMD0000000542 | BioModels
Project description:Aggregation of the microtubule-associated protein, tau, can lead to neurofibrillary tangle formation in neurons and glia, the hallmark of tauopathy. The cellular damages induced by the tau overexpression and aggregation may lead to multiple pathologic features of tauopathy. However, the effect of aging on tauopathy has not been elucidated yet. Here, we conducted lncRNA/mRNA sequencing analysis on P301S mutant Tau transgenic mouse model (PS19) with different ages to track the genetic changes occurred by the aging and progression of tau overexpression.
2019-06-23 | GSE118473 | GEO
Project description:Human non-mutated 0N4R Tau and P301L mutant 0N4R Tau tagged at the N-terminus with eGFP were expressed in mouse (CD1) primary cortical neurons using adeno associated viruses to monitor early changes in the synaptic interactome beforethe onset of neuronal loss. Affinity purification mass spectrometry (AP-MS) combined with tandem mass tagging was used to quantitatively compate the non-mutated and P301L interactomes.
2024-07-03 | PXD044959 | Pride
Project description:Many neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by abnormal protein deposition and frequently show comorbid pathology. Progranulin (PGRN) is implicated not only in TDP-43 but in tau and alpha-synuclein proteinopathies. However, the underlying mechanisms are unknown. Here, we generated P301S tau transgenic mice with PGRN haploinsufficiency and loss and found that those mice exhibit exacerbated disinhibition phenotype while showing attenuated memory impairment, hippocampal atrophy, and transcriptomic changes. Remarkably, the phenotypic alteration was accompanied by an increase in tau inclusions, which are positive for alpha-synuclein, a PGRN binding partner beta-glucocerebrosidase (GCase), and its substrate glucosylceramide. GCase inhibition or PGRN deficiency enhanced tau aggregation induced by AD-derived tau seeds in neurons. In vitro, GCase and glucosylceramide promoted P301S tau aggregation. Similar co-pathology was observed in AD and FTLD-GRN patients.
2024-01-18 | GSE180672 | GEO
Project description:Prions are composed of the misfolded prion protein (PrP(Sc)) organized in a variety of aggregates. An important question in the prion field has been to determine the identity of functional PrP(Sc) aggregates. In this study, we used equilibrium sedimentation in sucrose density gradients to separate PrP(Sc) aggregates from three hamster prion strains (Hyper, Drowsy, SSLOW) subjected to minimal manipulations. We show that PrP(Sc) aggregates distribute in a wide range of arrangements and the relative proportion of each species depends on the prion strain. We observed a direct correlation between the density of the predominant PrP(Sc) aggregates and the incubation periods for the strains studied. The relative presence of PrP(Sc) in fractions of different sucrose densities was indicative of the protein deposits present in the brain as analyzed by histology. Interestingly, no association was found between sensitivity to proteolytic degradation and aggregation profiles. Therefore, the organization of PrP molecules in terms of the density of aggregates generated may determine some of the particular strain properties, whereas others are independent from it. Our findings may contribute to understand the mechanisms of strain variation and the role of PrP(Sc) aggregates in prion-induced neurodegeneration.
| S-EPMC4753423 | biostudies-literature
Project description:Tau aggregates are critical pathological features of Alzheimer’s disease (AD) and other tauopathies. Growing evidence suggests that soluble tau aggregates trigger neurodegenerative phenotypes. However, the nature of the tau species and interactors involved in its aggregation and spreading remains unclear. By using size exclusion chromatography, mass spectrometry, and bioinformatic analysis, we identified Bassoon protein (BSN) as a significant tau interactor in PS19 mice, as well as in human AD and PSP cases. We also found that overexpression of BSN triggers the aggregation of tau and increase the tau seeding activity in vitro, and also exacerbates the degenerative phenotype in a Fly model for tauopathy. Knockdown of BSN significantly reduced tau spreading in PS19 mouse brains and destabilized the tau aggregates, leading to a reduction in the tau pathology in this model. Furthermore, BSN downregulation was able to restore the neurodegenerative phenotype in PS19 mice, observed in electrophysiology and behavioral tests. Our results identify BSN as a key interactor of tau spread and aggregation in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.
2023-03-11 | PXD027451 | Pride
Project description:Alzheimer's disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70/Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70/Hsp90 machinery forming a 710 kDa client-loading complex. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on Tau’s aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperone/substrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70/Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70/Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative disorders.
2022-08-11 | PXD032037 | Pride