Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA475562 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7290070_1.fastq.gz | Fastqsanger.gz | |||
| SRR7290070_2.fastq.gz | Fastqsanger.gz | |||
| SRR7290071.fastq.gz | Fastqsanger.gz | |||
| SRR7290072.fastq.gz | Fastqsanger.gz | |||
| SRR7290073.fastq.gz | Fastqsanger.gz |
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Project description:Transposable elements, known colloquially as “jumping genes,” constitute approximately 45% of the human genome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencing heterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance of transposable element transcripts. Here we identify transposable element activation as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders, including Alzheimer’s disease, that are pathologically characterized by deposits of tau protein in the brain. Mechanistically, we find that heterochromatin decondensation and reduction of piwi/piRNAs drive transposable element activation in tauopathy. Using genetic and pharmacological approaches in a Drosophila melanogaster model of tauopathy, we provide evidence for a causal relationship between pathogenic tau-induced heterochromatin decondensation, piwi/piRNA depletion, active transposable element obilization, and neurodegeneration. We further report a significant increase in transcripts of the endogenous retrovirus class of transposable elements in human Alzheimer’s disease and progressive supranuclear palsy, suggesting that transposable element dysregulation is conserved in human tauopathy. Taken together, our data identify heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element activation as a novel, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.
2018-07-04 | GSE115606 | GEO
Project description:Purpose: Overexpression of tau isoforms has been linked to neurodegenerative diseases, and abnormal tau expression is correlated with genomic instability. The purpose of this study is to use RNA-sequencing and molecular biological techniques to determine if there are any unique genomic consequences associated with overexpression of one or more tau isoforms. Methods: SHSY-5Y cells were infected in triplicate with lentiviruses to induce overexpression of 3R and 4R tau isoforms, were treated with amyloid-beta oligomers or DMSO, and were differentiated into neurons using retinoic acid. After RNA collection via TRIzol, poly(A)-selected, 100 bp, paired-end library preparation and sequencing were completed by the IGM Genomics Center, University of California, San Diego, La Jolla, CA, using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929). Trimmed FASTQ files were aligned to GRCH38 using STAR and differential expression of genes and transposable elements was determined using DESeq2 and software from TEToolkit (available from the Hammell Lab at Cold Spring Harbor Laboratory). Results: Our RNA-seq analysis revealed similar gene and transposable element expression patterns between cells overexpressing tau isoforms and patients with Alzheimer's disease or progressive supranuclear palsy. We found widespread differential expression particularly in L1 and Alu transposable elements and upregulation of genes related to extracellular matrix organization, focal adhesions, and cell junctions, among other biological processes. Conclusions: Our study is the first to our knowledge to examine locus-specific transposable element expression in the context of tauopathies, and to our knowledge is the first to specifically examine transposable element expression stemming from overexpression of tau isoforms. Our study provides additional evidence that transposable elements may play a role in tauopathies and provides further insight into the locations of transposable element expression in the genome in the context of neurodegenerative diseases.
2021-09-12 | GSE163150 | 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:Transposable elements, known colloquially as 'jumping genes', constitute approximately 45% of the human genome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencing heterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance of transposable element transcripts. Here we utilize Drosophila melanogaster and postmortem human brain samples to identify transposable element dysregulation as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologically characterized by deposits of tau protein in the brain. Mechanistically, we find that heterochromatin decondensation and reduction of piwi and piRNAs drive transposable element dysregulation in tauopathy. We further report a significant increase in transcripts of the endogenous retrovirus class of transposable elements in human Alzheimer's disease and progressive supranuclear palsy, suggesting that transposable element dysregulation is conserved in human tauopathy. Taken together, our data identify heterochromatin decondensation, piwi and piRNA depletion and consequent transposable element dysregulation as a pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.
| S-EPMC6095477 | biostudies-literature
Project description:The tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The type of tau isoforms (4R/3R) observed in brain aggregates is used to classify tauopathies. However, distinguishing tauopathies in cerebrospinal fluid remains challenging. Here, we demonstrated that the difference in tau isoforms between tauopathies is only observed in aggregates, not in soluble brain extracts. We therefore used untargeted mass spectrometry to characterize all post-translational modifications of both the aggregated and the soluble tau protein obtained from human brain tissue of patients with Alzheimer’s disease, cortico-basal degeneration, Pick’s disease, and fronto-temporal lobe degeneration. We found specific soluble signatures predictive of each tauopathy and its peculiar type of aggregated tau isoforms. These findings provide potential targets for developing cerebrospinal fluid assays able to distinguish between tauopathies in vivo. The comparison between soluble and aggregated tau features indicates potential mechanisms of tau aggregation, providing novel therapeutic leads for these diseases
2023-06-22 | PXD038901 | Pride
Project description:Increased G3BP2-Tau interaction in Tauopathies is a natural defense against Tau aggregation
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Project description:Pathological aggregation of RNA binding proteins (RBPs) has emerged as an important driver of multiple neurodegenerative diseases. Since RBP aggregation may result in a loss of normal RBP function, we examined whether dysregulation of RNA metabolism contributes to tauopathies. We find that the PS19 P301S tau mouse model exhibits a dysregulation of RNA splicing that is also apparent upon analysis of human Alzheimer’s disease brain tissues. Dysregulated splicing particularly affected genes involved in synaptic transmission. We also analyzed alternative splicing in PS19 mice crossed to a heterozygous TIA1 background, which has recently been shown to slow disease progression. TIA1 reduction alleviated several of the most significant alternative splicing events for synaptic mRNA transcripts, suggesting that normalization of RBP functions is associated with the neuroprotection. We then used a systems biology approach termed NetDecoder to identify key upstream biological targets, including MYC and EGFR, underlying the transcriptional and splicing changes in the protected compared to tauopathy mice. Importantly, pharmacological inhibition of MYC and EGFR activity in primary neurons overexpressing tau recapitulated the neuroprotective effects of TIA1 reduction. These results demonstrate that dysfunction of RBPs and RNA splicing processes are major elements of the pathophysiology of tauopathies, and identify new potential therapeutic targets for tauopathies.
2019-11-13 | GSE109226 | GEO
Project description:Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of Tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic acid-modified antisense oligonucleotides (LNA-ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3’UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well-tolerated and produced a robust, long lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post-injection and corresponded with tau protein reduction in the CSF. Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.
2022-08-04 | GSE204931 | GEO
Project description:Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of Tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic acid-modified antisense oligonucleotides (LNA-ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3’UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well-tolerated and produced a robust, long lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post-injection and corresponded with tau protein reduction in the CSF. Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.
2022-08-04 | GSE204930 | GEO
Project description:Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of Tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic acid-modified antisense oligonucleotides (LNA-ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3’UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well-tolerated and produced a robust, long lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post-injection and corresponded with tau protein reduction in the CSF. Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.
2022-08-07 | GSE209747 | GEO