Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA961689 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, that we further characterized by single nucleus RNA-sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.
2024-04-15 | GSE230447 | GEO
Project description:Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, that we further characterized by single nucleus RNA-sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.
2024-04-15 | GSE230519 | GEO
Project description:Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, that we further characterized by single nucleus RNA-sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.
2024-04-15 | GSE230450 | GEO
Project description:Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons
| PRJNA961691 | ENA
Project description:Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons
| PRJNA961142 | ENA
Project description:Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons
| PRJNA961152 | ENA
Project description:Methylation state of human post-mortem brain tissue from the frontal lobe of patients with Frontotemporal Dementia caused by mutations in GRN, MAPT and C9orf72 and healthy controls
2023-02-01 | E-MTAB-12674 | biostudies-arrayexpress
Project description:Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Systematic studies on human post-mortem brain tissue of patients with genetic subtypes of FTD are currently lacking. The Risk and Modyfing Factors of Frontotemporal Dementia (RiMod-FTD) consortium therefore has generated multi-omics datasets for genetic subtypes of FTD to identify common and distinct molecular mechanisms disturbed in disease. This experiment contains data from smRNA-sequencing of human post-mortem brain tissue of the frontal lobe from patients with FTD caused by mutations in GRN, MAPT or C9orf72 and healthy controls.
2023-02-26 | E-MTAB-12731 | biostudies-arrayexpress
Project description:INTRODUCTION: Frontotemporal dementia (FTD) is characterized by progressive atrophy of frontal and/or temporal cortices and considerable clinical, pathological, and genetic heterogeneity. METHODS: Frontal and temporal cortex tissues from FTD-GRN (n=9), FTD-MAPT (n=13), and non-demented controls (n=11) were analysed with quantitative proteomics (DIA). Expression-weighted cell type enrichment deduced the role of major brain cell types and gene ontology analysis identified distinct biological processes. FTD-MAPT data was also compared to an AD (n=10) protein signature. RESULTS: We identified brain region-specific FTD protein expression signatures. In frontal cortex of FTD-GRN, we observed immune processes in endothelial cells and mitochondrial dysregulation in neurons. In temporal cortex of FTD-MAPT, we observed dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairment. Comparison with AD indicated that alterations in RNA processing and oligodendrocyte function are distinct for FTD-MAPT. DISCUSSION: Our results indicate cell type-specific biological processes distinctive for genetic FTD subtypes. These findings may aid the development of FTD subtype-specific treatment strategies.
2022-08-12 | PXD031419 | Pride
Project description:Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices and an early age of onset. The disorder is highly heterogenic, comprising several genetic causes as well as a diverse phenotypic landscape of sporadic cases. Here we investigated the proteomic signatures of human brain frontal and temporal cortical lobes to identify key pathways involved in the three most frequent genetic subtypes of frontotemporal dementia. We included 38 patients with either an autosomal dominant repeat expansion in the C9ORF72 gene (n = 16), or a mutation in the GRN gene (n = 9) or the MAPT gene (n = 13), and 11 non-demented controls. Using data-independent quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for these genetic frontotemporal dementia subtypes compared to non-demented controls. Using published single cell RNA expression data for cell type enrichment we deduced the involvement of major brain cell types in driving these different protein signatures. Using gene ontology analysis, we identified distinct genetic subtype- and cell type-specific biological processes. In the GRN-mediated subtype, we observed higher protein expression related to immune processes, with a role for endothelial cells and astrocytes, and lower protein expression implicating mitochondrial dysregulation, primarily in neurons. In the MAPT-mediated subtype, we observed higher protein expression associated with dysregulation of RNA processing in multiple cell types, and lower protein expression implicating altered neuronal functioning via dysregulation of oligodendrocytes. Comparison of the MAPT-mediated frontotemporal dementia signature with one obtained from Alzheimer’s disease brains demonstrated only partial overlap in protein dysregulation, thus separating general neurodegenerative processes and highlighting the frontotemporal dementia-specific involvement of altered RNA processing and oligodendrocyte dysfunction. Taken together, our results indicate a role for different brain cell types and biological mechanisms in frontotemporal dementia, revealing both genetic subtype-specific processes, and processes shared with other neurodegenerative diseases such as Alzheimer’s disease.
2023-03-10 | PXD022872 | Pride