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Molecular Pathways are influenced by Progranulin in a neuronal cell model

ABSTRACT: Molecular Pathways are influenced by Progranulin in a neuronal cell model

PROVIDER: PRJNA771081 | ENA |

REPOSITORIES: ENA

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Molecular Pathways are influenced by Progranulin in a neuronal cell model

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

Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects.

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

Multiple Molecular Pathways Are Influenced by Progranulin in a Neuronal Cell Model-A Parallel Omics Approach.

Project description: Not available

| S-EPMC8791029 | biostudies-literature

Protein expression in the prefrontal cortex of aged mice with progranulin deficiency or neuronal progranulin overexpression

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

Multiple Molecular Pathways are influenced by Progranulin in a neuronal cell model

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

Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects.

2012-10-25 | GSE40378 | GEO

Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency Implicating Wnt Signaling

2011-09-01 | GSE31772 | GEO

Functional Genomic Analyses Identify Pathways Dysregulated by Progranulin Deficiency Implicating Wnt Signaling

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

Discovery of small molecules that normalize the transcriptome and enhance cysteine cathepsin activity in progranulin-deficient microglia

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

Effect of mouse and human progranulin haploinsufficiency on mouse cortical transcriptome at 18 months of age.

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

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