Molecular Pathways are influenced by Progranulin in a neuronal cell model
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ABSTRACT:
PROVIDER: PRJNA771081 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Gene expression microarrays were used to identify how the mRNA phenotype of NSC-34 cells responds to PGRN expression levels. PGRN expression correlated well with molecular phenotypes that included mRNA pathways associated with the regulation of the cytoskeleton Gene expression profile was determined using Illumina Mouse Whole-Genome Expression BeadChips (MouseWG-6 v2.0
2021-10-14 | GSE185877 | GEO
Project description:Multiple FTD patient-specific iPSC lines were generated for the first time, Human neurons of progranulin haploinsufficiency have been established. PGRN S116X neurons are more sensitive to kinase inhibitors-induced cell stress, which can be rescued by ectopic progranulin expression, revealing progranulin-dependent cellular defects in FTD. Microarray analysis reveals that the serine/threonine kinase S6K2 (RPS6KB2) and other genes involved in MAPK signaling are dysregulated specifically in neurons with progranulin deficiency. 32 independent human neuronal cultures were analyzed in this study
2012-10-25 | E-GEOD-40378 | biostudies-arrayexpress
Project description:Progranulin (PGRN) is critical in supporting a healthy CNS. Its haploinsufficiency results in frontotemporal dementia, while in experimental models of age-related neurodegenerative diseases, the targeted expression of PGRN greatly slows the onset of disease phenotypes. Nevertheless, much remains unclear about how PGRN affects its target cells. In previous studies we found that PGRN showed a remarkable ability to support the survival of NSC-34 motor neuron cells under conditions that would otherwise lead to their apoptosis. Here we used the same model to investigate other phenotypes of PGRN expression in NSC-34 cells. PGRN significantly influenced morphological differentiation, resulting in cells with enlarged cell bodies and extended projections. At a molecular level this correlated with pathways associated with the cytoskeleton and synaptic differentiation. Depletion of PGRN led to increased expression of several neurotrophic receptors, which may represent a homeostatic mechanism to compensate for loss of neurotrophic support from PGRN. The exception was RET, a neurotrophic tyrosine receptor kinase, which, when PGRN levels are high, shows increased expression and enhanced tyrosine phosphorylation. Other receptor tyrosine kinases also showed higher tyrosine phosphorylation when PGRN was elevated, suggesting a generalized enhancement of receptor activity. PGRN was found to bind to multiple plasma membrane proteins, including RET, as well as proteins in the ER/Golgi apparatus/lysosome pathway. Understanding how these various pathways contribute to PGRN action may provide routes toward improving neuroprotective therapies.
| S-EPMC8791029 | biostudies-literature
Project description:NSC-34 cells produced by fusing mouse embryonic spinal cord motor neuron with neuroblastoma cells expressing reduced level of PGRN (NSC-34/ShPGRN), NSC-34 cells overexpressing hPGRN(NSC-34-/hPGRN) or vector controls were compared in triplicate
2021-11-25 | MSV000088451 | MassIVE
Project description:Description: Progranulin deficiency is associated with neurodegeneration in humans and in mice. We performed a deep proteomic screen of the pre-frontal cortex in aged (13-15 months) female progranulin-deficient mice (GRN-/-) and mice with a neuron-specific inducible overexpression of progranulin (SLICK-GRN-OE with tamoxifen) versus the respective control mice (Grn+/+ and SLICK-Grn without Tamoxifen). The data set shows progranulin-dependent alterations of protein expression in the cortex of mice.
2016-10-13 | PXD004087 | Pride
Project description:Multiple FTD patient-specific iPSC lines were generated for the first time, Human neurons of progranulin haploinsufficiency have been established. PGRN S116X neurons are more sensitive to kinase inhibitors-induced cell stress, which can be rescued by ectopic progranulin expression, revealing progranulin-dependent cellular defects in FTD. Microarray analysis reveals that the serine/threonine kinase S6K2 (RPS6KB2) and other genes involved in MAPK signaling are dysregulated specifically in neurons with progranulin deficiency.
2012-10-25 | GSE40378 | GEO
Project description:Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted genome co-expression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes up-regulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potential therapeutic target.
2011-09-01 | GSE31772 | GEO
Project description:Progranulin (GRN) mutations cause frontotemporal dementia (FTD), but GRN's function in the CNS remains largely unknown. To identify the pathways downstream of GRN, we used weighted genome co-expression network analysis (WGCNA) to develop a systems-level view of transcriptional alterations in a human neural progenitor model of GRN-deficiency. This highlighted key pathways such as apoptosis and ubiquitination in GRN deficient human neurons, while revealing an unexpected major role for the Wnt signaling pathway, which was confirmed by analysis of gene expression data from postmortem FTD brain. Furthermore, we observed that the Wnt receptor Fzd2 was one of only a few genes up-regulated at 6 weeks in a GRN knockout mouse, and that FZD2 reduction caused increased apoptosis, while its upregulation promoted neuronal survival in vitro. Together, these in vitro and in vivo data point to an adaptive role for altered Wnt signaling in GRN deficiency-mediated FTD, representing a potential therapeutic target. We therefore developed an in vitro model of GRN deficiency using primary human neural stem cells in which shRNA was used to diminish GRN levels to 50% or below. We developed a tetracycline inducible system in which transactivator protein rtTA3 and PuroR genes were constituitively expressed under the UBC promoter, while RFP and shRNA were regulated by an inducible tet-On CMV promoter (Gossen and Bujard, 1992). To control for off-target effects, two hairpins against GRN were used, and a scrambled hairpin was used as a control.
2011-08-31 | E-GEOD-31772 | biostudies-arrayexpress
Project description:Patients with frontotemporal dementia (FTD) resulting from granulin (GRN) haploinsufficiency have reduced levels of progranulin and exhibit dysregulation in inflammatory and lysosomal networks. Microglia produce high levels of progranulin, and reduction of progranulin in microglia alone is sufficient to recapitulate inflammation, lysosomal dysfunction, and hyperproliferation in a cell-autonomous manner. Therefore, targeting microglial dysfunction caused by progranulin insufficiency represents a potential therapeutic strategy to manage neurodegeneration in FTD. Limitations of current progranulin-enhancing strategies necessitate the discovery of new targets.To identify compounds that can reverse microglial defects in Grn-deficient mouse microglia, we performed a compound screen coupled with high throughput sequencing to assess key transcriptional changes in inflammatory and lysosomal pathways. Positive hits from this initial screen were then further narrowed down based on their ability to rescue cathepsin activity, a critical biochemical readout of lysosomal capacity. The screen identified nor-binaltorphimine dihydrochloride (nor-BNI) and dibutyryl-cAMP, sodium salt (DB-cAMP) as two phenotypic modulators of progranulin deficiency. In addition, nor-BNI and DB-cAMP also rescued cell cycle abnormalities in progranulin-deficient cells. These data highlight the potential of a transcription-based platform for drug screening, and advance two novel lead compounds for FTD.
2020-08-02 | GSE143144 | GEO
Project description:We performed RNAseq on mouse progranulin deficient and humanized mouse progranulin deficient cortical tissue at 18 months to investigate the functional differences between mouse and human progranulin and identify transcriptomic changes for therapeutic endpoints.
2023-04-28 | GSE205735 | GEO