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SARS-CoV-2 ORF3a expression in brain disrupts the autophagy-lysosomal pathway, impairs sphingolipid homeostasis and drives neuropathogenesis

ABSTRACT: SARS-CoV-2 ORF3a expression in brain disrupts the autophagy-lysosomal pathway, impairs sphingolipid homeostasis and drives neuropathogenesis

PROVIDER: PRJNA930473 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23309219_1.fastq.gz	Fastqsanger.gz
	SRR23309219_2.fastq.gz	Fastqsanger.gz
	SRR23309220_1.fastq.gz	Fastqsanger.gz
	SRR23309220_2.fastq.gz	Fastqsanger.gz
	SRR23309221_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

SARS-CoV-2 ORF3a expression in brain disrupts the autophagy-lysosomal pathway, impairs sphingolipid homeostasis and drives neuropathogenesis

Project description:Studied the neuropathological effects of SARS-CoV-2 open reading frame 3a (ORF3a) in mice. Gene expression profiling analysis using data obtained from RNA-seq of 12 samples from AAV-Control (n=6) and AAV-ORF3a (n=6) transduced to express ORF3a.

2023-08-29 | GSE224290 | GEO

A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest

Project description:A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest

| PRJNA418450 | ENA

Mefloquine disrupts cancer stem cells by inhibiting lysosomal RAB5/7 mediated mitophagy

Project description:Mefloquine disrupts cancer stem cells by inhibiting lysosomal RAB5/7 mediated mitophagy

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ATM loss disrupts the autophagy-lysosomal pathway.

Project description: Not available

| S-EPMC8386711 | biostudies-literature

Aortic gene expression profiles show how APOA-I levels modulate infammation, lysosomal activity and sphingolipid metabolism in murine atherosclerosis

Project description:HDL particles are known to possess several anti-atherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant and antiinflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Methods Eight weeks old EKO mice, EKO mice overexpressing human apoA-I (EKO/hA-I) and wild-type mice as controls were fed either Chow or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyse the transcriptome of the aorta of the three genotypes in each experimental condition. Results: In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of the immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway Conclusions. ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response

2020-12-22 | GSE163657 | GEO

Inhibiting sphingolipid synthesis improves outcomes and survival in GARP-mutant wobbler mouse, an ALS model

Project description:Defects of the endosomal and lysosomal systems have been increasingly linked to adult neurodegenerative diseases1,2. Deficiencies in the retrograde trafficking pathway between endosomes and the Golgi apparatus lead to forms of Alzheimer’s and Parkinson’s diseases in the case of retromer mutations, or to the rare progressive cerebello-cerebral atrophy type 2 (PCCA2) for mutations of the Golgi-associated retrograde protein (GARP) complex3. Mutations in GARP subunits lead to abnormal cellular lipid metabolism, with accumulation of sterol esters and sphingoid bases, and concomitant lysosomal dysfunction in yeast, murine, or human cells4,5. However, whether these lipid changes cause neurodegeneration and if so, which lipids are toxic, is unknown. Here, we show that GARP defects lead to global changes of cellular protein distribution, including missorting of numerous disease-linked enzymes of sphingolipid metabolism, and to the accumulation of sphingolipid intermediates in wobbler fibroblasts. Inhibiting sphingolipid synthesis in wobbler mice, a murine model of GARP deficiency with features of amyotrophic lateral sclerosis (ALS), improved wellness scores and grip strength, and increased lifespan. Our findings indicate that regulation of sphingolipids by the GARP complex is essential for neuronal health and suggest that inhibition of sphingolipid synthesis might provide a therapeutic strategy for treatment of neurodegenerative diseases due to defects in retrograde endosome-to-Golgi membrane trafficking.

2022-02-15 | PXD007981 | Pride

Galns-deficiency enhances lysosomal exocytosis and alters cartilage development in zebrafish

Project description:Lysosomes represent a heterogenous population of organelles whose optimal function is essential for early tissue development. The importance of this is evidenced by the number of inherited disorders, collectively called the lysosomal storage disorders (LSDs), caused by lysosomal dysfunction. While it is clear that macromolecular accumulation can adversely impact tissue development, the full breadth of downstream pathways driving pathology in these disorders is yet to be elucidated. Recent studies support the existence of mechanisms beyond lysosomal storage that profoundly influence early tissue formation. Among these, impaired mitochondrial function, oxidative stress, inflammation, and abnormal growth factor signaling have been linked to early pathology in multiple LSD. Studies in zebrafish models of mucolipidosis II and sialidosis identified a mechanism whereby inappropriate secretion of lysosomal cathepsins disrupts the TGF-ß related signaling pathways that control skeletal formation. Here we demonstrate that loss of galns (N-acetyl galactosamine-6-sulfatase) also enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Along with changes in the activity of several cathepsin proteases, enhanced exocytosis disrupts TGFß and BMP signaling altering cartilage and bone development in galnsm/m mutant larvae. Together these data suggest a role for altered growth factor signaling in MPSIVA skeletal pathology.

2026-02-06 | GSE300957 | GEO

S1P lyase deficiency disrupts lipid homeostasis in liver

Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases. Experiment Overall Design: RNA samples from liver for three sphingosine-1-phosphate lyase knock-out and three WT mice.

2010-02-05 | E-GEOD-18745 | biostudies-arrayexpress

Aortic gene expression profiles show how APOA-I levels modulate infammation, lysosomal activity and sphingolipid metabolism in murine atherosclerosis

Project description:Aortic gene expression profiles show how APOA-I levels modulate infammation, lysosomal activity and sphingolipid metabolism in murine atherosclerosis

| PRJNA687012 | ENA

A lysosome-plasma membrane-sphingolipid axis linking lysosomal storage to cell growth arrest

Project description:We used human fibroblasts loaded with sucrose as a simple model of lysosomal accumulation, and we verified by high-throughput RNA sequencing which processes were altered by the treatment at two different time points. Moreover, we hypothesized that ceramide production due to the ectopic catabolism of plasma-membrane glycosphingolipids is involved in cell cycle arrest upon sucrose treatment. To test this hypothesis, we treated sucrose-loaded fibroblasts with two specific inhibitors for the β-glucosidases GBA1 and GBA2, and analyzed the cell responses using high-throughput RNA sequence.

2019-11-06 | GSE106928 | GEO

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