Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuropathology panel]
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ABSTRACT:
PROVIDER: PRJNA648369 | ENA |
REPOSITORIES: ENA
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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 | GSE155065 | 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.
2020-07-25 | GSE155066 | GEO
Project description:Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuroinflammation panel]
| PRJNA648370 | ENA
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 | GSE237106 | GEO
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 | GSE237105 | GEO
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
Project description:The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivated VCP in murine postnatal forebrain neurons (VCP cKO). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulated features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.
2021-06-16 | GSE178257 | GEO
Project description:FTLD-U is the most common pathological correlate of the neurodegenerative dementia frontotemporal dementia; We used microarrays to perform global expression profiling of FTLD-U brain samples Experiment Overall Design: Postmortem brain samples were isolated from normal controls, FTLD-U patients with progranulin gene mutations (progranulin) and FTLD-U patients without progranulin gene mutations (sporadic). Regional dissections were carried out from frontal cortex, hippocampus, and cerebellum.
2008-10-26 | E-GEOD-13162 | biostudies-arrayexpress
Project description:FTLD is the third most common neurodegenerative condition, following only Alzheimer's and Parkinson's diseases. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TDP-43 immunoreactivity. Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryo-EM. Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of TMEM106B, a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.
2021-11-22 | MSV000088430 | MassIVE
Project description:Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear 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 GRN haploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, and TDP-43 pathology in single and double knockout animals. Grn-/- /Tmem106b-/- mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn-/- knockouts only occasionally show TDP-43 pathology, the double knockout mice exhibit deposition of phosphorylated TDP-43. Thus, a loss of function of TMEM106B may enhance the risk for GRN-associated FTLD by reduced protein turnover in the lysosomal/autophagic system.
| S-EPMC7534633 | biostudies-literature