A nuclear role of tau in control DNA damage repair
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE262820 | GEO | 2026/03/31
REPOSITORIES: GEO
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Project description:In Alzheimer's disease (AD) and other tauopathies, tau dissociates from microtubules and forms toxic aggregates that contribute to neurodegeneration. Although some of the pathological interactions of tau have been identified from postmortem brain tissue, these studies are limited by their inability to capture transient interactions. To investigate the interactome of aggregate-prone fragments of tau, we applied an in vitro proximity labeling technique using split TurboID fused with the tau microtubule repeat domain (TauRD), a core region implicated in tau aggregation. We characterized this split TurboID TauRD displaying the requirement for both ligase fragment co-expression for robust enzyme activity and nuclear and cytoplasmic localization of the recombinant proteins. Following enrichment of biotinylated proteins and mass spectrometry, we identified over 700 TauRD interactors. Gene ontology analysis of enriched TauRD interactors highlighted processes often dysregulated in tauopathies, including spliceosome complexes, RNA-binding proteins (RBPs), and nuclear speckles. These in vitro results were further supported by integrating the TauRD interactome data with human AD tau interactome datasets and protein co-expression networks from human AD and related tauopathies. This revealed an overlap with the in vitro TauRD interactome and several modules enriched with RBPs and increased in AD and PSP. These findings emphasize the importance of nuclear pathways in tau pathology, such as RNA splicing and nuclear-cytoplasmic transport and establishes the sTurbo TauRD system as a valuable tool for exploring the tau interactome.
2025-11-12 | PXD059716 | Pride
Project description:In Alzheimer's disease (AD) and other tauopathies, tau dissociates from microtubules and forms toxic aggregates that contribute to neurodegeneration. Although some of the pathological interactions of tau have been identified from postmortem brain tissue, these studies are limited by their inability to capture transient interactions. To investigate the interactome of aggregate-prone fragments of tau, we applied an in vitro proximity labeling technique using split TurboID fused with the tau microtubule repeat domain (TauRD), a core region implicated in tau aggregation. We characterized this split TurboID TauRD displaying the requirement for both ligase fragment co-expression for robust enzyme activity and nuclear and cytoplasmic localization of the recombinant proteins. Following enrichment of biotinylated proteins and mass spectrometry, we identified over 700 TauRD interactors. Gene ontology analysis of enriched TauRD interactors highlighted processes often dysregulated in tauopathies, including spliceosome complexes, RNA-binding proteins (RBPs), and nuclear speckles. These in vitro results were further supported by integrating the TauRD interactome data with human AD tau interactome datasets and protein co-expression networks from human AD and related tauopathies. This revealed an overlap with the in vitro TauRD interactome and several modules enriched with RBPs and increased in AD and PSP. These findings emphasize the importance of nuclear pathways in tau pathology, such as RNA splicing and nuclear-cytoplasmic transport and establishes the sTurbo TauRD system as a valuable tool for exploring the tau interactome.
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Project description:Human tauopathies including Alzheimer's disease are characterized by alterations in the post-translational modification (PTM) pattern of Tau, leading to the formation of insoluble aggregates, neuronal dysfunction and degeneration. We immunoprecipitated Tau from post-mortem brain tissue of early stage Alzheimer's disease patients and age-matched controls, and analyzed PTMs on this soluble pool of Tau protein. In addition to known serine, threonine and tyrosine phosphorylation events, we identified a number of previously unknown monomethylation events on lysines in both control and Alzheimer's patient tissues.
2021-09-09 | PXD017065 | Pride
Project description:Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation. To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells. Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells. Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.
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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:Aging somatic cells are characterized by specific chromosome aneuploidy. This work examines the role of DNA replication within the centromeres of chromosomes Y (ChrY) and 21 (Chr21). The aneuploidy of these two chromosomes is associated with Alzheimer's Disease (AD) pathology. Using human neural progenitor cells engineered to overexpress wild-type (wt) and pseudo-hyper-phosphorylated (php) Tau proteins, we developed a novel method to analyze replication dynamics in centromeric regions. Our findings reveal overexpression reduces the replication initiation events that are active within alpha satellite sequences in control condition. Mass spectrometry analysis on immunoprecipitated Tau identified nuclear interactors of Tau, particularly in its php form, which might directly influence chromatin architecture and gene expression. This research provides critical insights into the molecular mechanisms of aneuploidy in tauopathies.
2026-01-09 | GSE286931 | GEO
Project description:Neuroinflammation is one of the major neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia often co-exist in the same brain regions where tau protein accumulates as hyperphosphorylated and aggregated PHFs or neurofibrillary tangles (NFTs) within neurons in patients with AD and related tauopathies. However, the exact mechanisms how pathological tau could induce neuroinflammatory responses are not clear. In this study, we treated primary human microglia with purified human PHFs and performed RNA-sequence analysis.
2021-09-16 | E-MTAB-5742 | biostudies-arrayexpress
Project description:Aging somatic cells are characterized by specific chromosome aneuploidy. This work examines the role of DNA replication within the centromeres of chromosomes Y (ChrY) and 21 (Chr21). The aneuploidy of these two chromosomes is associated with Alzheimer's Disease (AD) pathology. Using human neural progenitor cells engineered to overexpress wild-type (wt) and pseudo-hyper-phosphorylated (php) Tau proteins, we developed a novel method to analyze replication dynamics in centromeric regions. Our findings reveal overexpression reduces the replication initiation events that are active within alpha satellite sequences in control condition. Mass spectrometry analysis on immunoprecipitated Tau identified nuclear interactors of Tau, particularly in its php form, which might directly influence chromatin architecture and gene expression. This research provides critical insights into the molecular mechanisms of aneuploidy in tauopathies.
2025-12-24 | PXD058752 | Pride
Project description:Tauopathies, such as Alzheimer’s disease and Frontotemporal Dementia, are common neurodegenerative diseases characterized by misfolding, hyperphosphorylation, and aggregation of Tau. Molecular mechanisms underlying Tauopathies are still poorly understood, which is in part due to a lack of human models autonomously developing major disease hallmarks. Formation of late-stage disease phenotypes may require adult Tau isoform expression, which contributes to Tau pathogenesis but is challenging to replicate in human stem-cell-derived systems, thus impeding research on underlying mechanisms and drug development. Here we show that induction of adult human brain-like 4R Tau isoform expression enables cell-intrinsic formation of late-stage Tauopathy hallmarks in iPSC-derived neurons engineered to contain synergistic Tau mutations, without exogenous sources of Tau pathology. Neurons accumulated seeding-competent, hyper-phosphorylated, fibrillar Tau in tangle-like structures. Furthermore, exclusive expression of mutant 4R in the absence of the 3R Tau isoform disproportionately intensified pathology, resulting in highly abundant Tau misfolding and aggregation. Finally, we provide proof-of-principle that our model can be translationally applied both to test chemical disease modulators and evaluate human Tau PET tracers. Collectively, our model corroborates the central role of 4R Tau isoform expression for pathogenesis in human neurons and enables novel investigations to elucidate mechanisms underlying human Tauopathy formation. Moreover, it may also serve as a platform supporting urgently needed development of disease-modifying drugs.
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Project description:Alzheimer’s disease and tauopathies are neurodegenerative disorders characterized by the alteration of neuronal homeostasis and aggregation of Tau protein. Tau is generally considered a protein involved in cytoskeletal stability and transport whose destabilization leads to neuronal dysfunction and death. Despite the knowledge about canonical roles of Tau, in recent years it has been observed that Tau is a key player in several neuronal functions. We previously described that Tau destabilization and nuclear delocalization alters the expression of glutamatergic genes mediating early neuronal damage. In this paper we propose that Tau is able to deeply affect the neuronal transcriptome and that its availability is associated to gene expression alterations occurring in developing intermediate AD phases. In addition, we identify the epigenetic pathway as strongly altered by Tau during AD progression.
2024-11-11 | GSE239956 | GEO