Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA-sequencing of human cerebral cortex
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA684945 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR13248200.fastq.gz | Fastqsanger.gz | |||
| SRR13248201.fastq.gz | Fastqsanger.gz | |||
| SRR13248202.fastq.gz | Fastqsanger.gz | |||
| SRR13248203.fastq.gz | Fastqsanger.gz |
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Project description:Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood–brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
2022-06-03 | GSE163122 | GEO
Project description:Frontotemporal dementia is the second most common form of presenile dementia and autosomal dominant inheritance is present in 20-30% of cases, with mutations in granulin (GRN) as a major cause. The exact pathophysiological mechanism by which GRN mutations lead to neurodegeneration is poorly understood. We aimed to identify novel cerebrospinal fluid (CSF) biomarkers in GRN-associated frontotemporal dementia using shotgun proteomics. We included CSF from presymptomatic and symptomatic GRN mutation carriers and healthy non-carriers (controls). We validated our discovery proteomics results in a large international cohort of GRN-mutation carriers and other forms of genetic FTD (C9orf72- and MAPT-mutation carriers) by parallel reaction monitoring.
2019-04-30 | PXD012178 | Pride
Project description:Frontotemporal dementia is the second most common form of presenile dementia and autosomal dominant inheritance is present in 20-30% of cases, with mutations in granulin (GRN) as a major cause. The exact pathophysiological mechanism by which GRN mutations lead to neurodegeneration is poorly understood. We aimed to identify novel cerebrospinal fluid (CSF) biomarkers in GRN-associated frontotemporal dementia using shotgun proteomics. We included CSF from presymptomatic and symptomatic GRN mutation carriers and healthy non-carriers (controls). We validated our discovery proteomics results in a large international cohort of GRN-mutation carriers and other forms of genetic FTD (C9orf72- and MAPT-mutation carriers) by parallel reaction monitoring.
2019-04-29 | PXD012179 | Pride
Project description:Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.
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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
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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
Project description:Frontotemporal dementia is a debilitating neurodegenerative disorder characterized by frontal and temporal lobe degeneration, resulting in behavioral changes, language difficulties, and cognitive decline. In this study, smallRNA sequencing was conducted on postmortem brain tissues obtained from FTD patients with GRN, MAPT, or C9ORF mutations, focusing on the frontal and temporal lobes. Our analysis identified miR-129-5p as consistently deregulated across all mutation conditions and brain regions. Functional investigations revealed a novel role of miR-129-5p in astrocytes, where its loss led to neuroinflammation and impaired neuronal support functions, including glutamate uptake. Depletion of miR-129-5p in astrocytes resulted in the loss of neuronal spines and altered neuronal network activity. These findings highlight miR-129-5p as a potential therapeutic target in neurodegenerative diseases and also sheds light on the role of astrocytes in Frontotemporal dementia pathogenesis.
2025-04-17 | GSE262895 | GEO
Project description:MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at single nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes.
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