Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice
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ABSTRACT:
PROVIDER: PRJNA796296 | ENA |
REPOSITORIES: ENA
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Project description:Age-related neurodegenerative diseases (NDDs) and neuronal dysfunction are associated with the aggregation and propagation of specific pathogenic protein species (e.g. Aβ, α-synuclein, tau). However, whether the disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation with its frequent outcome of random protein misfolding is sufficient to recapitulate many early features of NDDs, including proteostasis dysregulation, perturbed Ca2+ signalling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in abnormal behavioral changes reminiscent of early Alzheimer's disease (AD), such as learning and memory deficits, maladaptive responses to novel stimuli, spontaneous epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation. Ectopic hippocampal NPY expression and cerebral glucose hypometabolism (18F-fluorodeoxyglucose PET) were further signs of neuronal hyperexcitability. Collectively, our findings strongly suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs providing an alternative framework for understanding the initiation of Alzheimer’s disease.
2022-09-19 | GSE193459 | GEO
Project description:A hallmark of Alzheimer Disease is the accumulation of aggregation-prone amyloid beta peptides, which can assemble into smaller aggregates and deposit in the form of amyloid plaques. Here we used the recently introduced APPNL-F mouse model of Alzheimer Disease, which faithfully recapitulates the amyloid beta pathology of the disease, to identify early changes to the global proteome. Using a workflow that interrogated the brain proteome of these mice by quantitative mass spectrometry at five, ten and fifteen months of age.
2017-08-02 | PXD004439 | Pride
Project description:Error-free and error-prone DNA repair gene expression through reprogramming and passage in human iPS cells
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Project description:Long-read RNA sequencing (RNA-seq) holds great potential for characterizing transcriptome variation and full-length transcript isoforms, but the relatively high error rate of current long-read sequencing platforms poses a major challenge. We present ESPRESSO, a computational tool for robust discovery and quantification of transcript isoforms from error-prone long reads. ESPRESSO jointly considers alignments of all long reads aligned to a gene and uses error profiles of individual reads to improve the identification of splice junctions and the discovery of their corresponding transcript isoforms. On both a synthetic spike-in RNA sample and human RNA samples, ESPRESSO outperforms multiple contemporary tools in not only transcript isoform discovery but also transcript isoform quantification. In total, we generated and analyzed ~1.1 billion nanopore RNA-seq reads covering 30 human tissue samples and three human cell lines. ESPRESSO and its companion dataset provide a useful resource for studying the RNA repertoire of eukaryotic transcriptomes.
2022-10-14 | GSE192955 | GEO
Project description:Medical applications of human iPS cells(hiPSC) are evolving, but detailed elucidation of the mechanisms of reprogramming remains to be elucidated. Reprogramming is accompanied by an increase in the expression of related genes that maintain pluripotency, such as OCT3 /4 and NANOG. Also, through reprogramming, many CNVs and point mutation arise in genomes, which constitute a major barrier to the use of hiPSC for regenerative medicine. On the other hand, we recently found that DNA repair-related genes expression are altered through reprogramming, elevated expression of genes that accurately convey genomic information, such as homologous recombination (HR) and mismatch repair(MMR), and decreased expression of error-prone translesion Synthesis polymerase(TLS). Here, we confirmed this expression change in another cell-line, and further found that this expression change was maintained by overlapping passages as well as OCT3 /4 and NANOG. This suggests that changes in the expression of DNA repair-related genes associated with reprogramming and their maintenance may be new indicators of the quality control of cells exhibiting pluripotency.
2019-07-21 | GSE134441 | GEO
Project description:BACKGROUND: Deletion of the chromatin remodeler CHD1 is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability [1-3]. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear. DESIGN: To study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 WT and homozygous deleted human benign and PCa lines. We also developed patient-derived organoid cultures and screened patients with metastatic PCa for CHD1 loss. RESULTS: We demonstrate that CHD1 loss sensitizes cells to DNA damage and causes a synthetic lethal response to DNA damaging therapy in vivo, ex vivo and in a patient with metastatic PCa. Mechanistically, CHD1 loss leads to decreased error-free homologous recombination (HR) repair, which is compensated by increased error-prone non-homologous end joining (NHEJ) repair for DNA double-strand break (DSB) repair. CONCLUSIONS: Our study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ and suggest that CHD1 loss may contribute to genomic instability seen in this subset of PCa patients.
2017-07-26 | GSE84610 | GEO
Project description:Anti-cancer therapies have been limited by emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error‐prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease we observed upregulation of GAS6, while ablation of GAS6’s receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators.
2022-11-17 | GSE202342 | GEO
Project description:ESPRESSO: Robust discovery and quantification of transcript isoforms from error-prone long-read RNA-seq data
| PRJNA793881 | ENA
Project description:DNA replication is sensitive to damage in the template. To bypass lesions and complete replication, cells activate recombination-mediated (error-free) and translesion synthesis-mediated (error-prone) DNA damage tolerance pathways. Crucial for error-free DNA damage tolerance is template switching, which depends on the formation and resolution of damage-bypass intermediates consisting of sister chromatid junctions. Here we show that a chromatin architectural pathway involving the high mobility group box protein Hmo1 channels replication-associated lesions into the error-free DNA damage tolerance pathway mediated by Rad5 and PCNA polyubiquitylation, while preventing mutagenic bypass and toxic recombination. In the process of template switching, Hmo1 also promotes sister chromatid junction formation predominantly during replication. Its C-terminal tail, implicated in chromatin bending, facilitates the formation of catenations/hemicatenations and mediates the roles of Hmo1 in DNA damage tolerance pathway choice and sister chromatid junction formation. Together, the results suggest that replication-associated topological changes involving the molecular DNA bender, Hmo1, set the stage for dedicated repair reactions that limit errors during replication and impact on genome stability. BrdU and proteins ChIP-chip analyses analysis were carried out as described (Bermejo et al., 2009). Labelled probes were hybridized to Affymetrix S.cerevisiae Tiling 1.0 (P/N 900645) arrays and processed with TAS software.
2014-01-28 | E-GEOD-46260 | biostudies-arrayexpress