Zebrafish psen1
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB24858 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2304200_1.fastq.gz | Fastqsanger.gz | |||
| ERR2304200_2.fastq.gz | Fastqsanger.gz | |||
| ERR2304201_1.fastq.gz | Fastqsanger.gz | |||
| ERR2304201_2.fastq.gz | Fastqsanger.gz | |||
| ERR2304202_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:Early-onset familial Alzheimer’s disease (EOfAD) is promoted by dominant mutations, enabling the study of Alzheimer’s disease (AD) pathogenic mechanisms through generation of EOfAD-like mutations in animal models. In a previous study, we generated an EOfAD-like mutation, psen1Q96_K97del, in zebrafish and performed a transcriptome analysis comparing entire brains from 6-month-old wild type and heterozygous mutant fish. We identified predicted effects on mitochondrial function and endolysosomal acidification. Here we aimed to determine whether similar effects occur in 7 day post fertilization (dpf) zebrafish larvae that might be exploited in screening of chemical libraries to find ameliorative drugs. We generated clutches of wild type and heterozygous psen1Q96_K97del 7 dpf larvae using a paired-mating strategy to reduce extraneous genetic variation before performing a comparative transcriptome analysis. We identified 228 differentially expressed genes and performed Goseq analysis and gene set enrichment analysis (GSEA). This predicted a significant effect on oxidative phosphorylation, consistent with our earlier observations of predicted effects on ATP synthesis in adult heterozygous psen1Q96_K97del brains. The dysregulation of minichromosome maintenance protein complex (MCM) genes strongly contributed to predicted effects on DNA replication and the cell cycle and may explain earlier observations of genome instability due to PSEN1 mutation. The upregulation of crystallin gene expression may be a response to defective activity of mutant Psen1 protein in endolysosomal acidification. Extracellular matrix (ECM) related genes were downregulated, consistent with previous studies of EOfAD mutant iPSC neurons and postmortem late onset AD brains. Also, changes in expression of genes controlling iron ion transport were observed without identifiable changes in the prevalence of transcripts containing iron responsive elements (IREs) in their 3’ untranslated regions. These changes may, therefore, predispose to the apparent iron dyshomeostasis previously observed in 6-month-old heterozygous psen1Q96_K97del EOfAD-like mutant brains.
2020-04-15 | GSE148631 | GEO
Project description:Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease. 21 Samples were analyzed: 7 controls, 7 Early-onset Alzheimer's disease (AD) patients and 7 early-onset AD genetically determined by a mutation in PSEN1 gene.
2015-01-20 | E-GEOD-39420 | biostudies-arrayexpress
Project description:PSEN1 ΔE9 mutation causes a familial form of Alzheimer's disease. We have previously shown that human induced pluripotent stem cell (iPSC)-derived astrocytes carrying PSEN1 ΔE9 mutation exhibit transcriptional and functional abnormalities (Stem Cell Reports. 2017;9:1885-1897). Here we injected glial progenitors derived from 2 pairs of PSEN1 ΔE9 mutant- isogenic CTRL iPSCs intracerebroventricularly into newborn mice. At the age of 18 months, mouse hippocampi containing human cells (5 x PSEN1 ΔE9 + 6 x CTRL, all from male mice) were quickly dissected out and bulk RNA sequencing analysis was performed. Our results shed more light on the efffect of PSEN1 ΔE9 mutation on human glia in vivo as well as on the effect of the presence of mutant human glia on the surrounding healthy mouse cells.
2022-12-15 | GSE221027 | GEO
Project description:PRESENILIN 2 (PSEN2) is one of the genes mutated in early onset familial Alzheimer’s disease (EOfAD). PSEN2 shares significant amino acid sequence identity with another EOfAD-related gene PRESENILIN 1 (PSEN1), and partial functional redundancy is seen between these two genes. However, the complete range of functions of PSEN1 and PSEN2 is not yet understood. In this study, we performed targeted mutagenesis of the zebrafish psen2 gene to generate a premature termination codon close downstream of the translation start with the intention of creating a null mutation. Homozygotes for this mutation, psen2S4Ter, are viable and fertile, and adults do not show any gross pigmentation defects, arguing against significant loss of γ-secretase activity. Transcripts containing the S4Ter mutation do not appear to be destabilized by nonsense-mediated decay. Forced expression in zebrafish embryos of fusions of psen2S4Ter 5’ mRNA sequences with sequence encoding green fluorescent protein (GFP) indicated that the psen2S4Ter mutation permits utilization of cryptic, novel downstream translation start codons. These likely initiate translation of N-terminally truncated Psen2 proteins that obey the “reading frame preservation rule” of PRESENILIN EOfAD mutations. Transcriptome analysis of entire brains from a 6-month-old family of wild type, heterozygous and homozygous psen2S4Ter female siblings revealed profoundly dominant effects on gene expression likely indicating changes in mitochondrial and (possibly) ribosomal function.
2020-04-11 | GSE148468 | GEO
Project description:Background: Mutations in PRESENILIN 1 (PSEN1) which still produce a transcript encoding a full-length, but mutant protein are the most common cause of early-onset familial Alzheimer’s disease (EOfAD). The only frameshift mutations found in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutations, and how they lead to completely different diseases, remains largely unexplored. Objective: To identify the similarities and differences of the effects of heterozygosity for mutations in psen1 causing EOfAD (T428del) or fAI (W233fs) on the brain transcriptome of young adult zebrafish. Methods: RNA sequencing was performed with high read depth on mRNA isolated from the brains of young adult (6 month old) zebrafish arising from a single family which contained either a single, heterozygous EOfAD-like or fAI-like mutation in the endogenous psen1 gene, and their wild type siblings. Results: Both mutations appeared to downregulate genes encoding the ribosomal subunits, and upregulated genes involved in inflammation. Genes involved in energy metabolism appeared to only be affected in EOfAD-like mutants, while genes involved in Notch, Wnt and neutrophin signalling pathways were only significantly altered by the fAI-like mutation. Further investigation of direct transcriptional targets of Notch revealed an apparent increase in Notch signalling. Conclusion: We observed both common, and distinct effects on transcriptomes of the heterozygous mutants compared to their wild type siblings. The distinct effects observed may shed light to how these mutations give rise to completely different diseases.
2021-02-01 | GSE164466 | GEO
Project description:Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease.
2015-01-20 | GSE39420 | GEO
Project description:To prevent or ameliorate Alzheimer’s disease (AD) requires that we understand its molecular basis. AD develops over decades but detailed molecular analysis of AD brains is limited to postmortem tissue where the stresses initiating the disease may be obscured by compensatory responses and neurodegenerative processes. Rare, dominant mutations in a small number of genes drive early onset of familial AD (EOfAD). Numerous transgenic models of AD have been constructed in mouse and other organisms based on these mutant genes, but transcriptomic analysis of these models has raised serious doubts regarding their representation of the disease state. Objective: In the absence of an understanding of the molecular mechanism(s) underlying AD, we posit that the most valid approach is to model the human genetic state as closely as possible – i.e. to analyse single, heterozygous EOfAD-like mutations of endogenous genes in intact brains. We used genome editing to introduce an EOfAD-like mutation (Q96_K97del) into the endogenous presenilin 1 (psen1) gene of zebrafish. We analysed transcriptomes of young adult (6-month-old) entire brains from a family of heterozygous mutant and wild type sibling fish. Gene ontology (GO) analysis revealed effects on mitochondria, particularly ATP synthesis, and on ATP-dependent processes including vacuolar acidification.
2019-02-06 | GSE126096 | GEO
Project description:The ribosome is a translational apparatus that comprises about 80 ribosomal proteins and four rRNAs. Recent studies reported that ubiquitination of the ribosomal proteins plays a pivotal role in translational control and ribosome-associated quality control (RQC). However, little is known about the dynamics of ribosome ubiquitination under complex biological processes of multicellular organisms. To study ribosome ubiquitination during animal development, we generated a zebrafish strain that expresses a FLAG-tagged ribosomal protein Rpl36/eL36 from its endogenous locus. Combining affinity purification of ribosomes from rpl36-FLAG zebrafish embryos with immunoblotting analysis, we analyzed ribosome ubiquitination during zebrafish development. Our data showed that ubiquitination of ribosomal proteins dynamically changed as development proceeded. We further revealed that Znf598, an E3 ubiquitin ligase that triggers RQC, contributed to the ribosome ubiquitination during zebrafish development. LC-MS/MS analysis and immunoblotting analysis identified lysines 139 of ribosomal protein Rps10/eS10 as pivotal ubiquitination sites on the ribosome during development. Finally, we demonstrated that an Rps10 K139/140R mutation reduced overall ribosome ubiquitination pattern. Collectively, these results reveal dynamics and complexity of ribosome ubiquitination in zebrafish development.
2023-10-11 | PXD039560 | JPOST Repository
Project description:Neural cells are under immense pressure to maintain proper degradation of molecules using their endo-lysosomal pathway (ELP). In Alzheimer’s disease (AD), the gradual cognitive worsening of this age-related disorder is partially due to dysfunction of the ELP. However, AD is a complex disorder and how the genetic landscape eventually leads to AD is unclear. Sanfilippo syndrome childhood dementia (mucopolysaccharidosis type III, MPSIII) is an extreme consequence of ELP dysfunction, where inherited recessive mutations result in the inability to properly catabolise a particular polysaccharide, which ultimately accumulates and interferes with the function of the ELP. Unlike AD, Sanfilippo is genetically simple (all causative genes are identified). The primary biochemical consequences are understood and animal models of Sanfilippo are considered excellent models of the human disease. Since Sanfilippo and AD show similar pathological changes, they likely share disease-associated mechanisms. Here, we dissect the similarity between AD and Sanfilippo using RNA-seq. We have generated zebrafish knock-in models of both diseases: the early-onset familial AD-like (EOfAD-like) mutation psen1 Q96_K97del and the MPSIII-like mutation naglu A603fs. We generated a family of zebrafish containing wild type, heterozygous EOfAD-like and homozygous MPSIII-like genotypes. We raised the family until 7 days post fertilisation and performed mRNA-seq on n = 8 induvial larvae per genotype. A power calculation revealed that this experiment was only contained ~50% power to detect differentially expressed genes. Nevertheless, changes to the expression of genes encoding proteins involved in lysosomal function could be detected in the MPS-III mutant larvae, suggesting a homeostatic response as the cells which make up the larval RNA-seq samples respond to dysfunctional lysosomes.
2022-11-08 | GSE217196 | GEO
Project description:Endothelial cells were isolated by flow cytometry using a specific marker (CD31) and their global gene expression profile was analyzed. CD11b marker was contraselected. This data were used to study molecular mechanisms implicated in endothelial cells from App/Psen1 mouse model. In this dataset, we include the expression data obtained in endothelial cells from APP/Psen1 (18 month-old) mouse model using a specific marker for this cell type (CD31+). Functional enrichment analyses were carried out through GSEA, where we have included specific categories potentially involved with blood vessel formation.
2021-03-22 | GSE121729 | GEO