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TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Human iMG]

ABSTRACT: TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Human iMG]

PROVIDER: PRJNA993719 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25239909.fastq.gz	Fastqsanger.gz
	SRR25239910.fastq.gz	Fastqsanger.gz
	SRR25239911.fastq.gz	Fastqsanger.gz
	SRR25239912.fastq.gz	Fastqsanger.gz
	SRR25239913.fastq.gz	Fastqsanger.gz

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Similar Datasets

TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Human iMG]

Project description:Heterozygous mutations in the granulin (GRN) gene result in haploinsufficiency of the progranulin (PGRN) protein, a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in the TMEM106B gene have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants are associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. In vitro, TMEM106B deletion did not reverse transcriptomic and proteomic profiles in GRN-deficient microglia, with the exception of a small set of immune-related proteins in the NF-κB pathway. In vivo, neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated gene expression in sorted microglia, lipid abnormalities, or histopathology in Grn knock-out mice. Furthermore, Tmem106b reduction with antisense oligonucleotide (ASO) treatment was poorly tolerated in Grn knock-out mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTLD-GRN.

2023-11-15 | GSE237104 | GEO

TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Mouse ASO]

2023-11-15 | GSE237105 | GEO

TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Mouse MG]

2023-11-15 | GSE237106 | GEO

TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models.

Project description:TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models.

| PRJNA993717 | ENA

TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Mouse ASO]

Project description:TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Mouse ASO]

| PRJNA993720 | ENA

TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Mouse MG]

Project description:TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models [Mouse MG]

| PRJNA993721 | ENA

TMEM106B reduction or partial depletion does not rescue GRN haploinsufficiency in mouse and iPSC-derived human microglia cell models.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-15 | GSE237107 | GEO

Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuroinflammation panel]

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.

2020-07-25 | GSE155066 | GEO

Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuropathology panel]

2020-07-25 | GSE155065 | GEO

TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models.

Project description:Heterozygous mutations in the granulin (GRN) gene are a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in TMEM106B have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here, we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. TMEM106B deletion did not reverse transcriptomic or proteomic profiles in GRN-deficient microglia, with a few exceptions in immune signaling markers. Neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated phenotypes in Grn -/-mice. Furthermore, Tmem106b reduction by antisense oligonucleotide (ASO) was poorly tolerated in Grn -/-mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTD-GRN.

| S-EPMC10641752 | biostudies-literature

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