Slowing prion disease via M1 muscarinic receptors is associated with reduced neuroinflammation and down-regulation of neurodegenerative disease markers
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ABSTRACT:
PROVIDER: PRJNA835325 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19091873_1.fastq.gz | Fastqsanger.gz | |||
| SRR19091873_2.fastq.gz | Fastqsanger.gz | |||
| SRR19091874_1.fastq.gz | Fastqsanger.gz | |||
| SRR19091874_2.fastq.gz | Fastqsanger.gz | |||
| SRR19091875_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: evaluation of the neuroprotective effects of VU846 compound, a positive allosteric modulator highly specific for the M1 muscarinic receptor, using the Next-generation sequencing (NGS) technology in a context of neurodegeneration induced by prion disease. Methods: Tg37 hemizygous mice at 3 to 4 weeks were inoculated with either the Rocky Mountain Laboratory (RML) scrapie prion brain homogenate, causative of the neurodegeneration, or normal brain homogenate for control purposes. Mice were also daily injected with either the M1 specific positive allosteric modulator VU836 or vehicle. The drug treatment started at 7week post brain homogenate inoculations (wpi) and 11wpi. The hippocampi from 3 mice of each group (control + vehicle, control + VU846, prion + vehicle and prion + VU846) were subject to tot RNA extraction. Raw reads were then converted into Fastq format, mapped to the “mouse-mm10” genome using HISAT2 (Galaxy Version 2.1.0) and processed with the StringTie (Galaxy Version 1.3.3.2) for assembling and quantification. Differential gene expression comparisons were performed with DESeq2 statistical tool (Galaxy Version 2.11.40.2) and data further analysed with two online software suites, Gene Ontology Panther (http://www.pantherdb.org/) and Pathway Studio (www.pathwaystudio.com). Results: we use the bioinformatic tool Pathway Studio (www.pathwaystudio.com) to quantitatively assesses the changes in the transcriptome with gene functions reported in the literature to assign an actication score. Strikingly, up and down regulation of genes changed by prion disease promote neuroinflammation and Alzheimer’s disease (AD) (positive activation scores), whereas the M1R specific positive allosteric modulator VU846 treatment modified the expression of genes to inhibit the neuroinflammatory and neurodegenerative processes directly associated with AD (negative activation score). Among these are genes associated with the complement system, microglia and astrocyte activation. Furthermore, consistent with the notion that neuroinflammatory pathways were activated in prion disease and diminished by VU846, the GO Pathway analysis revealed enrichment of genes in pathways such as the complement cascade and chemokine/cytokine signalling. Conversely, a group of genes that were down-regulated in prion disease were transcribed at significantly higher levels in the prion-effect of animals treated with VU846. These genes were strongly associated with synaptic plasticity, learning and memory, cognition and synaptic transmission by the GO Pathway analysis. Conclusions: These data point to the possibility that specific features of neuroinflammation and disease-adaptation may be directly regulated by M1-receptor activity strongly reinforcing the concept that pharmaceutically targeting M1 muscarinic receptor is neuroprotective and it might lead to the development of new treatments of Alzheimer’s like neurodegenerative diseases.
2023-05-04 | GSE202275 | GEO
Project description:Currently there are no treatments that can slow or halt the progression of dementia’s including Alzheimer’s disease. Here we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which shows many of the pathological hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulated as well as a normalisation in the expression of markers associated neurodegeneration and Alzheimer’s disease. Furthermore, synaptic proteins and post-synaptic signalling components disrupted in disease are maintained by VU846. We conclude that allosteric regulation of M1-receptors have the potential to reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.
2023-03-14 | PXD025561 | Pride
Project description:Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal, benign forms of prion protein (PrPC) to disease-causing PrPSc isoforms. A systems approach to disease postulates that disease arises from the pathological perturbation (genetic and/or environmental) of one or more biological networks in the relevant organ. In this regard, we tracked global (all mRNA transcripts) gene expression in the brains of eight distinct mouse strain-prion strain combinations at 8 - 10 time points throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Data are also available from http://prion.systemsbiology.net
2009-03-25 | E-MTAB-76 | biostudies-arrayexpress
Project description:Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly-treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.
2020-01-31 | GSE144028 | GEO
Project description:Understanding why certain neurons are more sensitive to dysfunction and death caused by misfolded proteins could provide therapeutically relevant insights into neurodegenerative disorders. Here, we harnessed single-cell transcriptomics to examine live neurons isolated from prion-infected female mice, aiming to identify and characterize prion-vulnerable neuronal subsets. Our analysis revealed distinct transcriptional responses across neuronal subsets, with a consistent pathway-level depletion of synaptic gene expression in damage-vulnerable neurons. By scoring neuronal damage based on the magnitude of depleted synaptic gene expression, we identified a diverse spectrum of prion-vulnerable glutamatergic, GABAergic, and medium spiny neurons. Comparison between prion-vulnerable and resistant neurons highlighted baseline gene expression differences that could influence neuronal vulnerability. For instance, the neuroprotective cold-shock protein Rbm3 exhibited higher baseline gene expression in prion-resistant neurons and was robustly upregulated across diverse neuronal classes upon prion infection. We also identified vulnerability-correlated transcripts that overlapped between prion and Alzheimer’s disease. Our findings not only demonstrate the potential of single-cell transcriptomics to identify damage-vulnerable neurons, but also provide molecular insights into neuronal vulnerability and highlight commonalties across neurodegenerative disorders.
2024-10-25 | GSE249382 | GEO
Project description:While prion infections have been extensively characterized in the laboratory mouse, little is known regarding the molecular responses to prions in other rodents. To explore these responses and make comparisons, we generated a prion disease in the laboratory rat by successive passage of mouse RML prions. Here we describe the accumulation of prions and associated pathology in the rat and describe the transcriptional impact throughout prion disease. Comparative transcriptional profiling between laboratory mice and rats suggests that similar molecular processes are unfolding in response to prion infection. At the level of individual transcripts, however, variability exists between mice and rats and many genes deregulated in mouse scrapie are not affected in rats. Notwithstanding these differences, many transcriptome responses are conserved between mice and rats infected with scrapie. Our findings highlight the usefulness of comparative approaches to understanding neurodegeneration and prion diseases in particular. We Adapted RML Mouse Scrapie into Rats and measured the resulting gene expression changes in brain as a result of disease progression. Rats were infected by intracranial inoculation with prion isolates obtained by adaptation of mouse RML scrapie prions into rats. Brain samples were collected from third and fourth passage infected rats and age-matched controls at specified timepoints and gene expression profiles obtained. For each time point, 3 diseased and control brain samples were profiled.
2015-09-01 | E-GEOD-63930 | biostudies-arrayexpress
Project description:While prion infections have been extensively characterized in the laboratory mouse, little is known regarding the molecular responses to prions in other rodents. To explore these responses and make comparisons, we generated a prion disease in the laboratory rat by successive passage of mouse RML prions. Here we describe the accumulation of prions and associated pathology in the rat and describe the transcriptional impact throughout prion disease. Comparative transcriptional profiling between laboratory mice and rats suggests that similar molecular processes are unfolding in response to prion infection. At the level of individual transcripts, however, variability exists between mice and rats and many genes deregulated in mouse scrapie are not affected in rats. Notwithstanding these differences, many transcriptome responses are conserved between mice and rats infected with scrapie. Our findings highlight the usefulness of comparative approaches to understanding neurodegeneration and prion diseases in particular.
2015-09-01 | GSE63930 | GEO
Project description:Cytoplasmic RNA granules have emerged as important elements of posttranscriptional and translational regulation. Stress, germinal and neuronal granules contain RNA-binding proteins capable of self-assembly due to prion-like domains. Hyperassembly mediated by these prion-like domains causes several neurodegenerative diseases. Here, we report a subset of the mammalian prion protein (PrP), also prone to self-assembly, propagation and to cause devastating diseases, is a component of naturally occurring messenger ribonucleoproteins (mRNPs) in adult mouse brains. Biomolecules co-purified with PrP revealed a multitude of diverse RNA granule associated proteins and mRNAs encoding members of the translation machinery, indicating a role in a specialized translation process. Importantly, PrP mutations linked to Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI) severely impaired recovery of mRNPs from preclinical mice, possibly representing a very early pathological process. Thus, mutant PrP may cause dysfunction in RNA regulation, thereby joining the constantly expanding ranks of disease associated RNP granule proteins. The file Enrichment_analysis.xlsx contains mRNAs (FDR < 0.01) co-purified with PrP in both WT sample pools as identified by DESeq2 and the respective gene counts and log2 fold changes for CJD and FFI PrP:IP sample pools.
2015-11-01 | GSE57233 | GEO
Project description:Human prion diseases are fatal neurodegenerative disorders characterized by neuronal damage in brain. Protein S-nitrosylation, the covalent adduction of a NO to cysteine, plays a role in human brain biology, and brain dysfunction is a prominent feature of pPrion disease, yet the direct brain targets of S-nitrosylation are largely unknown. We described the first proteomic analysis of global S-nitrosylation in brain tissues of sporadic Creutzfeldt–Jakob disease (sCJD), fatal familial insomnia (FFI) and genetic CJD with a substitution of valine for glycine at codon 114 of the prion protein gene (G114V gCJD) accompanying with normal control with isobaric tags for relative and absolute quantitation (iTRAQ) combined with a nano-HPLC/Q Exactive Mass spectrometry platform. In parallel, we used several approaches to provide quality control for the experimentally defined S-nitrosylated proteins. Total 1509 S-nitrosylated proteins (SNO-proteins) were identified, and cerebellum tissues appeared to contain more commonly differentially expressed SNO-proteins (DESPs) than cortex of sCJD, FFI and gCJD. Three selected SNO-proteins were verified by Western blots, consistent with proteomics assays. Gene ontology analysis showed that more up-regulated DESPs were involved in metabolism, cell cytoskeleton/structure and immune system both in cortex and cerebellum, while more down-regulated ones in both regions were involved in cell cytoskeleton/structure, cell-cell communication and miscelaneous function protein. Pathway analysis suggested that systemic lupus erythematosus, pathogenic Escherichia coli infection, extracellular matrix-receptor interaction were the most commonly affected pathways, which were identified from at least two different diseases. Using STRING database, the network of immune system and cell cytoskeleton and structure were commonly identified in the context of the up-regulated and down-regulated DESPs, respectively, both in cortex and cerebellum. Our study thus have implications for understanding the molecular mechanisms of human prion diseases related to abnormal protein S-nitrosylation and pave the way for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases.
2017-03-29 | MSV000080756 | MassIVE
Project description:Cytoplasmic RNA granules have emerged as important elements of posttranscriptional and translational regulation. Stress, germinal and neuronal granules contain RNA-binding proteins capable of self-assembly due to prion-like domains. Hyperassembly mediated by these prion-like domains causes several neurodegenerative diseases. Here, we report a subset of the mammalian prion protein (PrP), also prone to self-assembly, propagation and to cause devastating diseases, is a component of naturally occurring messenger ribonucleoproteins (mRNPs) in adult mouse brains. Biomolecules co-purified with PrP revealed a multitude of diverse RNA granule associated proteins and mRNAs encoding members of the translation machinery, indicating a role in a specialized translation process. Importantly, PrP mutations linked to Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI) severely impaired recovery of mRNPs from preclinical mice, possibly representing a very early pathological process. Thus, mutant PrP may cause dysfunction in RNA regulation, thereby joining the constantly expanding ranks of disease associated RNP granule proteins. The file Enrichment_analysis.xlsx contains mRNAs (FDR < 0.01) co-purified with PrP in both WT sample pools as identified by DESeq2 and the respective gene counts and log2 fold changes for CJD and FFI PrP:IP sample pools. RIP-Seq analysis of mRNAs co-purified with PrP from murine brain cytoplasmic fractions in wild-type (WT), CJD and FFI mice. Each RIP-Seq and control (input) library represents a pool of 12 to 16 co-immunoprecipitation samples out of 3 to 4 mice. To control for post-homogenization artifacts, we conducted an experiment in which we prepared homogenates from WT and PrP-KO (Prnp-/-) mice of different genetic backgrounds (C57BL/6 and 129S4) and identified SNPs in RIP-Seq and control libraries to finally identify specifically co-purified mRNAs.
2015-11-01 | E-GEOD-57233 | biostudies-arrayexpress