Gene Expression Study in Progranulin-Deficient Mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE31840 | GEO | 2011/09/01
SECONDARY ACCESSION(S): PRJNA145105
REPOSITORIES: GEO
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Project description:Study of brain regions from GRN KO, Heterozygous and WT mice at different time points (2-6-9 months) Cortex, cerebellum and hippocampus were dissected and studied at 2-6-9 months from KO (-/-), Het (-/+), and WT (+/+) animals
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Project description:PGRN is involved in lysosomal function and is expressed in the brain. Grn knock-out (KO) mice develop several pathologies including lysosomal lipi accumulation, gliosis and neurodegeneration. Here we seek to determine if we can rescue Grn KO pathologies with a peripherally delivered AAV, that targets the liver, and drives expression of full length PGRN fused to a mouse TfR binding scFv (AAV(L):bPGRN. The PGRN fusion protein expressed by this AAV (8D3:PGRN), is brain penetrant. To study this, Grn KO mice were given a single IV injection of either saline or AAV(L):bPGRN at 4 months of age. After 8 months when the mice were 12 months of age, brain samples were collected and bulk RNA sequencing was performed to assess correction of transcriptional changes. Grn wild type (WT) mice treated with saline were also included as a control.
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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.
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Project description:GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.
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Project description:GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.
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Project description:In this study, we investigated the role of Tet2 in regulation of hematopoietic genes by performing transcriptomic analysis of Tet2 WT, Mut, and KO LSK and Lin– cells at 3, 6, 9, and 12 months by RNA-seq, and mapping the DNA methylation landscape of 3-month-old Tet2 WT, Mut, and KO LSK and Lin– cells. (1) We find that loss of Tet2 (Tet2 KO) vs. a loss of Tet2 catalytic function (Tet2 Mut) at different time points and cell types causes distinct gene expression changes when compared to WT samples as assessed by RNA-seq. (2) Additionally, we find that many genes implicated in lymphoma and leukemia are deregulated in Tet2 Mut and KO LSK and Lin– cells, consistent with the phenotypes observed in mice transplanted with Tet2 Mut and KO bone marrow. (3) We also mapped genome-wide DNA methylation levels of WT, Tet2 Mut, and KO LSK and Lin– cells at 3 months by WGBS and establish a role for Tet2 in demethylating genes implicated in lymphoma and leukemia initiation and progression.
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Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.
2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
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:Polygenic risk factors influence onset and progression of neurodegenerative diseases, but are difficult to be functionally explored in isolation. Single nucleotide polymorphisms (SNPs) in TMEM106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN mutation carriers. Currently, it is not clear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss-of-function of TMEM106B is responsible for the increased disease risk of patients with PGRN haploinsufficiency. We therefore compared behavioral abnormalities, gene expression patterns, lysosomal activity and TDP-43 pathology in single and double knockout animals. Grn–/–/Tmem106b–/– mice showed a strongly reduced life span and massive motor deficits. Gene expression analysis revealed an upregulation of molecular signatures characteristic for disease associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as a pronounced accumulation of ubiquitinated proteins and wide spread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn–/– knockouts only occasionally showed TDP-43 pathology, the double knockout mice exhibit robust deposition of phosphorylated TDP-43. Thus, a loss-of-function of TMEM106B may enhance the risk for GRN-associated FTD by reduced protein turnover in the lysosomal/autophagic system.
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