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PubMed2023

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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes injury to multiple organ systems, including the brain. SARS-CoV-2's neuropathological mechanisms may include systemic inflammation and hypoxia, as well as direct cell damage resulting from viral infections of neurons and glia. How the virus directly causes injury to brain cells, acutely and over the long term, is not well understood. In order to gain insight into this process, we studied the neuropathological effects of open reading frame 3a (ORF3a), a SARS-CoV-2 accessory protein that is a key pathological factor of the virus. Forced ORF3a brain expression in mice caused the rapid onset of neurological impairment, neurodegeneration, and neuroinflammation-key neuropathological features found in coronavirus disease (COVID-19, which is caused by SARS-CoV-2 infection). Furthermore, ORF3a expression blocked autophagy progression in the brain and caused the neuronal accumulation of α-synuclein and glycosphingolipids, all of which are linked to neurodegenerative disease. Studies with ORF3-expressing HeLa cells confirmed that ORF3a disrupted the autophagy-lysosomal pathway and blocked glycosphingolipid degradation, resulting in their accumulation. These findings indicate that, in the event of neuroinvasion by SARS-CoV-2, ORF3a expression in brain cells may drive neuropathogenesis and be an important mediator of both short- and long-term neurological manifestations of COVID-19.

Animals↗
PubMed1990

Sphingolipid metabolism in organotypic mouse keratinocyte cultures.

Ceramides are the dominant component of the stratum corneum intercellular lipid lamellae, which constitute the epidermal permeability barrier. Only pig and human epidermal ceramides have been extensively characterized and the structures of the ceramides of cultured keratinocytes have not been previously investigated. In the present studies, we have characterized the ceramides synthesized by organotypic lifted mouse keratinocyte cultures for the first time and compared them to the ceramides of intact mouse epidermis. Both mouse epidermis and cultures contained five ceramides, ceramide 1 being the least polar and ceramide 5 the most polar. Ceramide 1 was a group of acylceramides, i.e., very-long-chain omega-hydroxyceramides with an ester-linked nonhydroxy fatty acid. Ceramide 2 contained medium-length saturated nonhydroxy fatty acids. (In culture, the ceramide 2 band was split into two parts with the slightly more polar ceramide 2' containing short-chain saturated nonhydroxy fatty acids.) Ceramide 5 contained short-chain alpha-hydroxy fatty acids. The structures of ceramides 1, 2, and 5 were analagous to those of pig and human epidermis. Mouse epidermal ceramide 3 was quite unusual, containing beta-hydroxy fatty acids, a structure not previously identified among mammalian ceramides. In contrast, culture ceramide 3 was composed of omega-hydroxy fatty acids with a chain-length distribution similar to that of ceramide 1. Mouse ceramide 4 was composed of fatty acids with chromatographic mobility similar to hydroxy fatty acids but with different chemical reactivity; it remains only partially characterized. Culture ceramide 4 was present in quantities too small for analysis. All ceramides in mouse epidermis and cultures contained only sphingosine bases, whereas pig and human ceramides also contain phytosphingosine. These results indicate that considerable diversity of ceramide structures occurs among mammalian species and that cultured keratinocytes may only partially reproduce the in vivo complement of ceramides. Using labeled serine in keratinocyte cultures, we have also demonstrated the de novo synthesis of ceramides and the transfer of label from glucosylceramides to ceramides during terminal differentiation of lifted cultures. The covalently bound corneocyte lipid envelope, which has recently been characterized in pig and human epidermis, was also present in mouse epidermis and was reproduced by the lifted cultures. Very-long-chain omega-hydroxyceramides were the dominant bound lipid and labeling studies in culture indicated that they were derived from ceramides synthesized in the viable epidermis.

Animals↗
PubMed1998

Coupling of the p75 neurotrophin receptor to sphingolipid signaling.

The neurotrophins are a family of growth factors involved in the survival and differentiation of specific populations of neurons and glial cells. Many of the trophic signals elicited by neurotrophins are initiated by the binding of these molecules to various Trk tyrosine kinase receptors. In contrast, recent data suggest that neurotrophin-mediated death signals are generated through the interaction of nerve growth factor with the low-affinity neurotrophin receptor, p75NTR, Neurotrophins may signal through p75NTR by stimulating sphingomyelin hydrolysis and generating ceramide in primary cultures of neurons and glial cells as well as in fibroblasts heterologously expressing p75NTR. The biochemical characteristics of p75NTR-dependent ceramide generation are discussed relative to the role of ceramide in p75NTR-dependent apoptosis and the activation of NF-kappa B.

Animals↗
PubMed1998

Sphingolipids as receptor modulators. An overview.

Glycosphingolipids are amphipathic compounds that exist mainly in the plasmalemma with their oligosaccharide portion protruding into the extracellular environment. In this position they are admirably situated for interacting with both ligands and receptors. Binding studies have demonstrated that specific glycolipids function as receptors for some microorganisms and bacterial toxins. Specific oligosaccharides on both glycolipids and glycoproteins bind members of the selection families, and some gangliosides facilitate integrins binding to their ligands. Gangliosides modulate the trophic factor-stimulated dimerization, tyrosine phosphorylation, and subsequent signal transduction events of several tyrosine kinase receptors. GM3 inhibits both the epidermal growth factor receptor and basic fibroblast factor receptor; several gangliosides except GM3 inhibit the platelet-derived growth-factor receptor; GM1 enhances nerve growth-factor-stimulated activation of TrkA; insulin receptor is inhibited to varying degrees by several gangliosides, but 2-->3 sialosylparagloboside is most effective. Activities of the beta(1)-adrenergic and delta-opioid receptors are modulated by GM1. Available information suggests that glycolipids serve as coordinators of multiple receptor functions.

Animals↗
PubMed1971

Sphingolipids.

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Animals↗
PubMed1984

Sphingolipid metabolism during infection of human fibroblasts by herpes simplex virus type 1.

Results from several experiments support the view that sphingomyelin turnover and glycosphingolipid synthesis play a role in herpes simplex virus infection of cells in culture. Inhibition of sphingomyelinase by phosphatidylcholine or by a synthetic ceramide, N-palmitoyl-DL-dihydrosphingosine, interferes substantially with virus reproduction as does a genetic defect in the enzyme (Niemann-Pick disease). In Niemann-Pick cells, yields of infectious virus are about 3% of the normal level. An inhibitor of ceramide: UDP glucose glucosyltransferase was also used to test the effect of altered glycosphingolipid synthesis on infection. This compound, DL-2-decanoylamino-3-morpholinopropiophenone, decreased virus yields to a level about 0.1% of normal at the highest concentration tested.

Cells, Cultured↗