Mus musculus
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD005138
PROVIDER: PRJNA352400 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4896160_1.fastq.gz | Fastqsanger.gz | |||
| SRR4896160_2.fastq.gz | Fastqsanger.gz | |||
| SRR4896170_1.fastq.gz | Fastqsanger.gz | |||
| SRR4896170_2.fastq.gz | Fastqsanger.gz | |||
| SRR4896180_1.fastq.gz | Fastqsanger.gz |
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Project description:To gain insight into how mutant Huntingtin (mHTT) CAG repeat length may modify Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat length. We find repeat length dependent transcriptional signatures are prominent in the striatum, less so in cortex, and minimal in the liver. Co-expression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age, and that are preserved in HD models and some in the patients. Top striatal modules implicate mHTT CAG length and age in graded impairment of striatal medium spiny neuron identity gene expression and in dysregulation of cAMP signaling, cell death, and protocadherin genes. Importantly, we used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at both RNA and protein levels and validated 21 striatal module genes as modifiers of mHtt toxicities in vivo.
2016-02-16 | PXD003442 | Pride
Project description:Using Huntington’s disease (HD) mouse models that quantitatively replicate the reduction of striatal Phoshodiesterase 10 (PDE10) levels in manifest Huntington’s disease patients, we demonstrate the potential therapeutic benefit of PDE10 inhibition on correcting basal ganglia circuitry deficits thought to drive disease symptomology in patients. PDE10 inhibition acutely restored corticostriatal input and boosted cortically driven indirect pathway activity in HD models with compromised PDE10 levels. We show that cyclic nucleotide signaling processes are impaired in the models, and that elevation of both the cAMP and cGMP nucleotides afforded by PDE10 inhibition are required for this rescue. Global phosphoproteomic profiling of striatal proteins in response to PDE10 inhibition provide novel information on the plausible neural substrates responsible for the improvement. Finally, we show that long-term chronic treatment of the Q175 knock-in mouse model with PDE10A inhibitors, starting at a presymptomatic age, showed improvements, above and beyond those seen during acute administration, including a partial reversal of striatal deregulated transcripts predominantly driven through activation of the AP-1 and CREB transcription factor complexes, and a prevention of the emergence of some cardinal HD neurophysiological deficits.
2016-12-02 | PXD005138 | Pride
Project description:Here we analyse transcriptome profiles within the frontal cortex between wild type, heterozygous and homozygous TDP-43 Q331K knock-in mice
2018-03-08 | GSE99353 | GEO
Project description:Human genetics as well as pharmacological intervention reveal that Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by stalling the ribosome near codon 34 of its messenger RNA. Inhibition by PF-06446846 is sensitive to the amino acid sequence of the PCSK9 nascent chain, and not the messenger RNA. PF-06446846 also reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling to examine the proteome-wide effects of PF-06446846, we find that it is exceptionally specific for PCSK9 and has no measurable effect on 99.7% of the translatome at concentrations sufficient for 90% inhibition of PCSK9 expression. Together, PF-06446846 represents the first example of an orally administered small molecule directly targeting PCSK9 that functions by a mechanism inhibiting translation during elongation with a high degree of selectivity. Selective inhibition of translation in human may represent a new approach to target proteins with small molecules.
2017-03-27 | PXD005835 | Pride
Project description:Human genetics as well as pharmacological intervention reveal that Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by stalling the ribosome near codon 34 of its messenger RNA. Inhibition by PF-06446846 is sensitive to the amino acid sequence of the PCSK9 nascent chain, and not the messenger RNA. PF-06446846 also reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling to examine the proteome-wide effects of PF-06446846, we find that it is exceptionally specific for PCSK9 and has no measurable effect on 99.7% of the translatome at concentrations sufficient for 90% inhibition of PCSK9 expression. Together, PF-06446846 represents the first example of an orally administered small molecule directly targeting PCSK9 that functions by a mechanism inhibiting translation during elongation with a high degree of selectivity. Selective inhibition of translation in human may represent a new approach to target proteins with small molecules.
2017-03-27 | PXD005822 | Pride
Project description:BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington’s disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD. METHODS: We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 asymptomatic HD, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment. RESULTS: We identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to processes relating to nervous system development and transcriptional regulation. CONCLUSIONS: These results demonstrate that miRNA expression in cortical BA9 provides insight into striatal involvement and support a role for these miRNAs, particularly miR-10b-5p, in HD pathogenicity. The miRNAs identified in our studies of postmortem brain tissue may be detectable in peripheral fluids and thus warrant consideration as accessible biomarkers for disease stage, rate of progression, and other important clinical characteristics of HD. 26 Huntington's disease, 2 asymptomatic HD gene positive and 49 neurologically normal control prefrontal cortex samples
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Project description:Forkhead box protein P1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in CNS development, but its role in the mature brain is unknown. In order to ascertain functional roles for Foxp1 in the CNS, we have identified gene targets for Foxp1 in vitro using gene expression microarrays and chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) assays. Transcriptome-wide analysis of Foxp1-transfected striatal cells revealed widespread expression changes of genes related to immune signaling, cancer, transcriptional regulation, and a curated Huntington’s disease (HD) signaling pathway. Integrating the microarray expression dataset with Foxp1 binding sequences determined from ChIP-seq analysis resulted in 75 direct targets of Foxp1, which included Foxp1 itself, which were also related to immune processes and the category “genetic disorder”. These findings demonstrate that Foxp1 is a primary transcriptional repressor of immunological-related gene expression in striatal cells. n=3 wt STHdh striatal cells and n=3 Foxp1-transfected STHdh striatal cells
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Project description:Selective degeneration of striatal projection neurons is one of the main features of Huntington’s disease (HD). The differences between vulnerable and resilient striatal cell types and cell type-specific molecular events associated with HD progression have not been established. Here we employed fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of different cell types of the human striatum in HD and control donors.
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Project description:LRRK2 mutations are associated with both familial and sporadic forms of Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 plays critical roles in regulating striatal function. Here, by using knock-in mouse lines that express the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how pathogenic LRRK2 mutations altered striatal physiology. To identify the signaling pathways that underlie the motor learning deficits, specifically in the RC mice we performed six-plex tandem mass tag (TMT) quantitative mass spectrometry (MS) to compare the protein expression of either RC or GS and WT mice following the five days of the rotarod test.
2022-12-15 | PXD037003 | Pride
Project description:Shank3 is an abundant excitatory postsynaptic scaffolding proteins implicated in various neurodevelopmental and psychiatric disorders, including ASD, Phelan-McDermid syndrome, intellectual disability, and schizophrenia. Shank3-mutant mice with a homozygous deletion of exons 14-16 (Shank3-HM mice) show ASD-like behavioral deficits and altered synaptic and neuronal functions, but little is known about how different ages, brain regions, and gene dosages contribute to transcriptomic phenotypes in these mice. Here, we performed RNA-Seq-based transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank3 heterozygous- and homozygous-mutant mice. In addition, juvenile and adult Shank3 homozygous-mutant forebrain transcriptomes were compared. Juvenile and adult forebrain transcriptomes from Shank3 homozygous-mutant mice showed the patterns that are opposite and similar to those observed in ASD: reverse-ASD and ASD-like patterns, respectively. Here, the juvenile reverse-ASD pattern involved synaptic gene upregulations and ribosomal and mitochondrial downregulations, whereas the adult ASD-like pattern involved opposite changes. Gene set enrichment analyses (GSEA) of brain regional transcripts in adult Shank3-HT and Shank3-HM mice revealed that the cortical, hippocampal, and striatal transcripts show distinctly altered biological functions and ASD-related/risk gene expressions. The cortex and striatum display ASD-like patterns whereas the hippocampus displays reverse-ASD patterns. The cortical ASD-like pattern more strongly involves ASD-risk genes whereas the striatal ASD-like pattern more strongly involves astrocyte/microglia genes. Shank3-HT and Shank3-HM transcripts in a given brain region display largely similar patterns in biological functions and ASD-related/risk gene expressions, suggestive of small gene dosage effects. These results suggest that heterozygous and homozygous Shank3 deletions in mice lead to age, brain region, and gene dosage-differential transcriptomic changes.
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