Use of mice defective in interferon signaling to distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease
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ABSTRACT:
PROVIDER: PRJNA631692 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR11768300.fastq.gz | Fastqsanger.gz | |||
| SRR11768301.fastq.gz | Fastqsanger.gz | |||
| SRR11768288.fastq.gz | Fastqsanger.gz | |||
| SRR11768289.fastq.gz | Fastqsanger.gz | |||
| SRR11768290.fastq.gz | Fastqsanger.gz |
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Project description:The type 1 interferon (IFN) response is part of the innate immune response and best known for its role in viral and bacterial infection. However, this pathway is also induced in sterile inflammation such as occurs in a number of neurodegenerative diseases, including neuronopathic Gaucher disease (nGD), a lysosomal storage disorder (LSD) caused by mutations in Gba1. Mice were injected with conduritol B-epoxide, an irreversible inhibitor of acid-beta glucosidase, the enzyme defective in nGD. Quadrat deficient MyTrMaSt mice, where four adaptors of pathogen recognition receptors (PRRs) are deficient, were used to determine the role of the IFN pathway in nGD pathology. Activation of inflammatory and other pathways was analyzed by a variety of methods including RNAseq. Elevation in the expression of PRRs associated with the IFN response was observed in CBE-injected mice. Ablation of upstream pathways leading to IFN production had no therapeutic benefit on the lifespan of nGD mice but attenuated neuroinflammation. Primary and secondary pathological pathways, i.e. those associated or not with mouse lifespan, were distinguished, and a set of ~210 genes including those related to sphingolipid, cholesterol and lipoprotein metabolism, along with a number of inflammatory pathways related to chemokines, TNF, TGF, complement, IL6 and damage associated pathogens were classified as primary pathological pathways, along with some lysosomal and neuronal genes. Although IFN signaling is the top elevated pathway in nGD, we demonstrate that this pathway is not related to mouse viability and is consequently defined as a secondary pathology pathway. By elimination, we defined a number of critical pathways that are directly related to brain pathology in nGD, which in addition to its usefulness in understanding pathophysiological mechanisms may also pave the way for development of novel therapeutic paradigms by targeting such pathways.
2020-09-01 | GSE150266 | GEO
Project description:Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels. Moreover, GPNMB levels in the CSF correlate with disease severity in a mouse model of Gaucher disease. GPNMB was also elevated in brain samples from patients with type 2 and 3 Gaucher disease. Our data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy once suitable treatments towards the neurological symptoms of Gaucher disease become available.
2016-06-24 | PXD001654 | Pride
Project description:Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood-brain barrier. However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation. We now induce nGD in mice by injection with conduritol B-epoxide (CBE), an irreversible inhibitor of acid beta-glucosidase (GCase), the enzyme defective in nGD, with or without co-injection with GZ-667161, a prototype for SRT. Significant neuropathology, and a reduction in lifespan, was observed upon CBE injection, and this was largely reversed by co-injection with GZ-667161, along with a reduction in glucosylceramide and glucosylsphingosine levels. Analysis of gene expression by RNAseq revealed that GZ-667161 largely reversed the changes in genes and pathways that were differentially-expressed upon CBE injection, specifically pathways of GSL metabolism, lipoproteins and other lipid metabolic pathways, lipid droplets, astrocyte activation, neuronal function, and to some extent, neuroinflammation. Together, this demonstrates the efficacy of SRT to reverse the effects of substrate accumulation on pathological components and pathways in nGD brain.
2020-05-26 | GSE151133 | GEO
Project description:BackgroundThe type 1 interferon (IFN) response is part of the innate immune response and best known for its role in viral and bacterial infection. However, this pathway is also induced in sterile inflammation such as that which occurs in a number of neurodegenerative diseases, including neuronopathic Gaucher disease (nGD), a lysosomal storage disorder (LSD) caused by mutations in GBA.MethodsMice were injected with conduritol B-epoxide, an irreversible inhibitor of acid beta-glucosidase, the enzyme defective in nGD. MyTrMaSt null mice, where four adaptors of pathogen recognition receptors (PRRs) are deficient, were used to determine the role of the IFN pathway in nGD pathology. Activation of inflammatory and other pathways was analyzed by a variety of methods including RNAseq.ResultsElevation in the expression of PRRs associated with the IFN response was observed in CBE-injected mice. Ablation of upstream pathways leading to IFN production had no therapeutic benefit on the lifespan of nGD mice but attenuated neuroinflammation. Primary and secondary pathological pathways (i.e., those associated or not with mouse survival) were distinguished, and a set of ~210 genes including those related to sphingolipid, cholesterol, and lipoprotein metabolism, along with a number of inflammatory pathways related to chemokines, TNF, TGF, complement, IL6, and damage-associated microglia were classified as primary pathological pathways, along with some lysosomal and neuronal genes.ConclusionsAlthough IFN signaling is the top elevated pathway in nGD, we demonstrate that this pathway is not related to mouse viability and is consequently defined as a secondary pathology pathway. By elimination, we defined a number of critical pathways that are directly related to brain pathology in nGD, which in addition to its usefulness in understanding pathophysiological mechanisms, may also pave the way for the development of novel therapeutic paradigms by targeting such pathways.
| S-EPMC7487497 | biostudies-literature
Project description:Neuroinflammation is a key phenomenon in the pathogenesis of many neurodegenerative diseases. Understanding the mechanisms by which brain inflammation is engaged and delineating the key players in the immune response and their contribution to brain pathology is of great importance for the identification of novel therapeutic targets for these devastating diseases. Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the GBA1 gene and is a significant risk factor for Parkinson?s disease; in some forms of Gaucher disease, neuroinflammation is observed. An unbiased gene profile analysis was performed on a severely affected brain area of a neurological form of a Gaucher disease mouse at a pre-symptomatic stage; the mouse used for this study, the Gbaflox/flox; nestin-Cre mouse, was engineered such that GBA1 deficiency is restricted to cells of neuronal lineage, i.e., neurons and macroglia. The 10 most up-regulated genes in the ventral posteromedial/posterolateral region of the thalamus were inflammatory genes, with the gene expression signature significantly enriched in interferon signaling genes. Our results imply that the type I interferon response is involved in the development of nGD pathology, and support the notion that interferon signaling pathways play a vital role in the sterile inflammation that often occurs during chronic neurodegenerative diseases in which neuroinflammation is present.
2016-05-19 | GSE46866 | GEO
Project description:Gaucher disease, a recessive inherited metabolic disorder caused by defects in the gene encoding glucosylceramidase (GlcCerase), can be divided into three subtypes according to the appearance of symptoms associated with central nervous system involvement. We now identify a protein, glycoprotein non-metastatic B (GPNMB), that acts as an authentic marker of brain pathology in neurological forms of Gaucher disease. Using three independent techniques, including quantitative global proteomic analysis of cerebrospinal fluid (CSF) in samples from Gaucher disease patients that display neurological symptoms, we demonstrate a correlation between the severity of symptoms and GPNMB levels. Moreover, GPNMB levels in the CSF correlate with disease severity in a mouse model of Gaucher disease. GPNMB was also elevated in brain samples from patients with type 2 and 3 Gaucher disease. Our data suggest that GPNMB can be used as a marker to quantify neuropathology in Gaucher disease patients and as a marker of treatment efficacy once suitable treatments towards the neurological symptoms of Gaucher disease become available.
2017-03-29 | MSV000080786 | MassIVE
Project description:Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently-discovered genetic relationship with Parkinson’s disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid β-glucosidase (GCase) using the irreversible inhibitor, conduritol-B-epoxide (CBE), is particularly attractive, although few systematic studies examining the effect of CBE on development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on the dose of CBE and its time of injection. Gene array analysis shows a remarkable similarly in the gene expression profile of CBE-treated mice and a genetic GD mouse model, the Gbaflox/flox;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up regulated in Gbaflox/flox;nestin-Cre mice. Finally, we demonstrate that some aspects neuropathology and some behavioral abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD, which will prove particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time consuming crossing of mice.
2016-08-30 | GSE78757 | GEO
Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela-treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks and were sacrificed one week after the injection for RNA isolation from different tissues like liver, lung and spleen.
2013-09-07 | E-GEOD-44569 | biostudies-arrayexpress
Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela- treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks. To understand the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela).
2013-09-07 | E-GEOD-44640 | biostudies-arrayexpress
Project description:Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela-treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy
2013-09-07 | GSE44569 | GEO