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

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

PROVIDER: PRJNA599087 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10829931.fastq.gz	Fastqsanger.gz
	SRR10829932.fastq.gz	Fastqsanger.gz
	SRR10829933.fastq.gz	Fastqsanger.gz
	SRR10829934.fastq.gz	Fastqsanger.gz
	SRR10829935.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

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

| PRJNA599087 | ENA

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

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.

| S-EPMC7426857 | 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

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

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

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

2012-10-25 | GSE40378 | GEO

Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation

Project description:Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

2022-08-01 | GSE188498 | GEO

Altered Ca+2 homeostasis induces Calpain-Cathepsin axis activation in sCJD.

Project description:Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrPSc). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca+2) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis. Here we describe the presence of massive regulation of Ca+2 responsive genes in sCJD brain tissue, accompanied by two Ca+2-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Calpain 1 treatment enhances seeding activity of PrPSc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons. Additionally, massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca+2 homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model. Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.

2017-05-15 | GSE90977 | GEO

Effect of Cathepsin L exposure on endothelial cell transcriptomics

Project description:Cathepsin L is a lysosomal protease that is secreted by several cancer cells. Cathepsin L upregulation has been widely associated with poor clinical outcome and increased metastatic incidence. However, whether Cathepsin L participates in tumor angiogenesis remains less studied. Our study showed a significant activation of angiogenic capacity of endothelial cells in presence of purified or tumor derived Cathepsin L. In addition, Cathepsin L exposure led to a significant increase in the proliferative capacity of endothelial cells. While the ability of Cathepsin L to promote endothelial cell sprouting, migration, invasion and tube formation can be attributed to its proteolytic effects on extracellular matrix, how it promotes endothelial cell proliferation remains obscure. The objective of this study was to test if Cathepsin L exposure can activate signaling cascades and gene expression leading to proliferation of endothelial cells.

2016-06-20 | GSE75744 | GEO

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