Transcriptomic signatures of oxytosis/ferroptosis are enriched in Alzheimer’s disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1168515 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30873100.fastq.gz | Fastqsanger.gz | |||
| SRR30873101.fastq.gz | Fastqsanger.gz | |||
| SRR30873102.fastq.gz | Fastqsanger.gz | |||
| SRR30873103.fastq.gz | Fastqsanger.gz | |||
| SRR30873104.fastq.gz | Fastqsanger.gz |
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Project description:Oxytosis/ferroptosis is a non-apoptotic regulated cell death pathway characterized by glutathione (GSH) depletion with consequent inhibition of the GSH-dependent enzyme GSH peroxidase 4 (Gpx4), activation of lipoxygenases (LOXs), production of reactive oxygen species (ROS) and mitochondrial dysfunction, that culminates in cell death. Most of these changes are observed with aging and exacerbated in Alzheimer’s disease (AD). Furthermore, it has been shown that novel inhibitors of oxytosis/ferroptosis are protective in mouse models of aging and AD. One of the most potent of these inhibitors is the neuroprotective compound CMS121. The goal of the present study was to investigate the occurrence of oxytosis/ferroptosis in the AD brain by examining transcriptomic signatures of oxytosis/ferroptosis in multiple cellular and animal models of AD as well as in human AD brain samples. Our data show that different signatures of oxytosis/ferroptosis are enriched to varying extents in the brains of AD mice and human AD patients.
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Project description:Chemical Checker (CC) is a resource that provides processed, harmonized and integrated bioactivity data on 800,000 small molecules. In the CC, bioactivity data are expressed in a vector format, which naturally extends the notion of chemical similarity between compounds to similarities between bioactivity signatures of different kinds. We experimentally validate that CC signatures can be used to reverse and mimic biological signatures of disease models and genetic perturbations. We developed cellular models of Alzheimer’s disease (AD) by introducing familial AD (fAD) mutations into SH-SY5Y cells. Using CRISPR/Cas9-induced homology-directed repair, we obtained clones harboring the fAD PSEN1-M146V or the APP-V717F mutations. Three compounds (noscapine - 10 uM, palbociclib - 0.4 uM and AG-494 - 10uM) reverted fAD signatures. We confirmed that genes up-regulated in SH-SY5Y fAD mutants were indeed downregulated upon treatment with the drugs, and vice versa. Moreover, the three drug treatments significantly reverted a subset of genes strongly linked to AD, including the recovery of the expression levels of GRIN2D, a glutamate receptor involved in synaptic transmission and BIN1, a gene involved in synaptic vesicle endocytosis and strongly associated with AD risk.
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Project description:Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers. Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.
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