Loss of homeostatic functions in microglia from a murine model of Friedreich’s ataxia
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ABSTRACT:
PROVIDER: PRJNA974033 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24651742.fastq.gz | Fastqsanger.gz | |||
| SRR24651743.fastq.gz | Fastqsanger.gz | |||
| SRR24651744.fastq.gz | Fastqsanger.gz | |||
| SRR24651745.fastq.gz | Fastqsanger.gz | |||
| SRR24651746.fastq.gz | Fastqsanger.gz |
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Project description:Background Friedreich’s ataxia (FRDA) is a rare genetic disorder characterized by motor discoordination and predominant cerebellar involvement. It is caused by mutations leading to decreased transcription of frataxin (FXN), a gene encoding for a mitochondrial protein involved in the biogenesis of iron-sulfur clusters and iron handling. Many advances have been achieved in understanding the pathophysiology of FRDA and the mechanisms whereby FXN deficiency causes cerebellar degeneration. However, the issue concerning the contribution of central nervous system-resident non-neuronal cells to the pathogenesis of FRDA is still poorly explored. In this work, we set out to verify if specific vulnerabilities of cerebellar microglia could be involved in the pathogenesis of FRDA. Methods Primary cerebellar microglia were obtained from the KIKO mouse model of FRDA. We analyzed their phenotype and functions by a multilayer study, encompassing morphological analysis, migration and phagocytosis assays, gene expression by RNA-seq, RT-PCR, western blot, and immunofluorescence. Mitochondria functionality was evaluated by flow cytometry and real-time metabolic analysis. We assessed the effect of FRDA microglia on cell viability and neurite length in primary neurons. We analyzed in vivo microglia phenotype in the cerebellum of KIKO miceduring an early developmental stage by means of morphology analysis, RT-PCR and immunofluorescence. Results We demonstrated that FRDA microglia exhibit traceable morphological, transcriptional and functional changes, particularly regarding inflammatory pathways and mitochondria functionality. In addition, we found that FRDA microglia impair neuron survival and neurite length in vitro. Finally, we showed that cerebellar microglia in vivo exhibit dysregulations at early postnatal age of FRDA mice. Conclusions These results indicate that FRDA microglia display aberrant features and may participate in neuron dysfunction, evidencing a non-cell-autonomous mechanism in FRDA. Therefore, microglia targeting could be a valuable strategy in ameliorating cerebellar degeneration in the disease.
2024-08-26 | GSE232826 | GEO
Project description:Functional enrichment analysis of differentially expressed genes reveals alteration of visceral adipose tissue resembling type 2 diabetes signatures in a mouse model of Friedreich’s ataxia
2023-09-08 | GSE239980 | GEO
Project description:Martin et al. JCI Insigh (2017). Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action is via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s Ataxia cardiomyopathy mouse model (FXNKO). At baseline, the FXNKO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXNKO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3KO and SIRT3KO/FXNKO (dKO) knockout models. The improvement in cardiac function upon NMN treatment in the FXNKO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio- protection, SIRT3 mediates NMN-induced improvements in both cardiac and extra-cardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich’s Ataxia patients.
2017-07-21 | PXD006754 | Pride
Project description:Friedreich’s ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal, but display a loss of motor coordination and cardiac abnormalities. Many ultimately succumb to heart failure. Administration of nicotinamide adenine dinucleotide (NAD+) precursors has shown promise in mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not “fail” per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of Friedreich’s Ataxia and warrant further investigation.
2024-08-28 | GSE271798 | GEO
Project description:Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers, an important goal of translational research in neurodegeneration. Friedreich’s Ataxia (FRDA) is a chronic neurodegenerative disease caused by reduced transcription of frataxin, a ubiquitously expressed protein. We studied in vitro lymphocytes from FRDA patients and carriers, in order to identify a peripheral gene expression phenotype. Peripheral biomarkers related to disease status would be extremely valuable for assessing drug efficacy and could provide new pathophysiological insights. We identified a subset of genes changed in cells from patients with pathological frataxin deficiency and a core set of these genes were confirmed in independent series. Changes in gene expression were related to the mitochondria, lipid metabolism, cell cycle, and DNA repair, consistent with FRDA’s known pathophysiology. We evaluated the in vitro effect of multiple compounds (HDAC inhibitors) on this putative biomarker set, and found that this biochemical phenotype was ameliorated in accordance with drug efficacy. Frataxin downregulation is associated with robust changes in gene expression in PBMCs, providing pathogenetic insights and a core subset of genes which, if verified in vivo, could be used as a peripheral biomarker. We characterized the gene expression profiles in peripheral blood mononuclear cells (PBMCs) from FRDA patients, compared with controls and related carriers. Cells were studied both before and after in vitro treatment with compounds that increase frataxin levels. Quantitative real-time PCR and additional microarrays were used to confirm a core set of genes in multiple independent series
2011-07-25 | E-GEOD-30933 | biostudies-arrayexpress
Project description:The inherited neurodegenerative disease Friedreich’s ataxia (FRDA) is caused by hyperexpansion of GAA•TTC trinucleotide repeats within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAA•TTC repeats causes heterochromatin-mediated silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts through retroviral transduction of transcription factors. FXN gene repression is maintained in the iPSCs, as are the mRNA and miRNA global expression signatures reflecting the human disease. GAA•TTC repeats uniquely in FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme Msh2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in the iPSCs, occupies FXN intron 1, and shRNA silencing of Msh2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.
2010-07-02 | GSE22651 | GEO
Project description:Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers, an important goal of translational research in neurodegeneration. Friedreich’s Ataxia (FRDA) is a chronic neurodegenerative disease caused by reduced transcription of frataxin, a ubiquitously expressed protein. We studied in vitro lymphocytes from FRDA patients and carriers, in order to identify a peripheral gene expression phenotype. Peripheral biomarkers related to disease status would be extremely valuable for assessing drug efficacy and could provide new pathophysiological insights. We identified a subset of genes changed in cells from patients with pathological frataxin deficiency and a core set of these genes were confirmed in independent series. Changes in gene expression were related to the mitochondria, lipid metabolism, cell cycle, and DNA repair, consistent with FRDA’s known pathophysiology. We evaluated the in vitro effect of multiple compounds (HDAC inhibitors) on this putative biomarker set, and found that this biochemical phenotype was ameliorated in accordance with drug efficacy. Frataxin downregulation is associated with robust changes in gene expression in PBMCs, providing pathogenetic insights and a core subset of genes which, if verified in vivo, could be used as a peripheral biomarker.
2011-07-26 | GSE30933 | GEO
Project description:Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n=11) and control brain (n=14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.
2023-07-09 | GSE236268 | GEO
Project description:APOE4 retinal microglia remain homeostatic in glaucoma.
| PRJNA791674 | ENA
Project description:To compare microglial regional heterogeneity, we generated bulk RNA-seq profiles of postnatal day 60 microglia, sorted by TMEM119+ (also CD45lowCD11b+), from cortex (CTX), cerebellum (CB), hippocampus (HIP), striatum (STR) regions. For each sample, 3000 microglia were FACS sorted into RLT lysis buffer for total RNA extraction, followed by Smart-seq library preparation and Illumina Nextseq (sequence depth 10-20 million per sample). Consistent with our scRNA-seq data, samples from 4 regions were highly correlated (R>0.99), and individual samples did not cluster according to tissue origins, suggesting striking similarities between homeostatic microglia from different brain regions. Moreover, we could not detect any differentially expressed genes (FDR < 0.05) between regions from the bulk samples. These data suggest that classical adult microglia with homeostatic signatures (e.g. Tmem119), as the most dominant microglial population in the healthy brain, have little transcriptomic heterogeneity across brain regions.
2018-12-31 | GSE123021 | GEO