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Sphingolipid Metabolism and Signaling in Diseases 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 31568

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Dr. Paola Giussani

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Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, LITA Segrate, Via Fratelli Cervi, 93, 20090 Segrate, Italy
Interests: sphingolipids; sphingosine-1-phosphate; ceramide; signaling; cancer; multiple sclerosis
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Dear Colleagues,

It is now well known that sphingolipids are not only ubiquitous components of cell membranes but also have emerged as bioactive molecules involved in the control of cell fate. Sphingolipids have been shown to be involved in signal transduction and, consequently, in the regulation of a huge number of physiological and pathophysiological processes such as cell proliferation, survival, death, differentiation, migration, and invasiveness. The dysregulation of sphingolipid metabolism and signaling is associated with and contributes to the pathogenesis of numerous pathologies, including inflammation, cancer, diabetes, neurodegenerative diseases, and cystic fibrosis. The control of sphingolipid levels can be achieved through the regulation of specific enzymes of their metabolism as well as of the specific transporters or receptors involved in their transport within or outside the cells. The exact molecular mechanisms mediated by sphingolipids to modulate the cellular effects are still not completely understood, and new knowledge on the metabolism and signaling of sphingolipids will help in further understanding the role of sphingolipids in a variety of physiopathological conditions.

For the Special Issue “Sphingolipids Metabolism and Signaling in Diseases”, we welcome your contributions in the form of original research and review articles on all aspects of sphingolipids and their role in physiological and pathophysiological metabolic processes.

Dr. Paola Giussani
Guest Editor

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Keywords

sphingolipids
sphingosine-1-phosphate
ceramide
sphingolipid-mediated signaling
cancer
neurodegenerative diseases
inflammatory diseases
diabetes
cystic fibrosis

Related Special Issue

Sphingolipid Metabolism and Signaling in Diseases in International Journal of Molecular Sciences (23 articles)

Published Papers (13 papers)

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22 pages, 4033 KiB

Open AccessArticle

Sphingosine as a New Antifungal Agent against Candida and Aspergillus spp.

by Fahimeh Hashemi Arani, Stephanie Kadow, Melanie Kramer, Simone Keitsch, Lisa Kirchhoff, Fabian Schumacher, Burkhard Kleuser, Peter-Michael Rath, Erich Gulbins and Alexander Carpinteiro

Int. J. Mol. Sci. 2022, 23(24), 15510; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415510 - 07 Dec 2022

Cited by 3 | Viewed by 1543

Abstract

This study investigated whether sphingosine is effective as prophylaxis against Aspergillus spp. and Candida spp. In vitro experiments showed that sphingosine is very efficacious against A. fumigatus and Nakeomyces glabrataa (formerly named C. glabrata). A mouse model of invasive aspergillosis showed that sphingosine exerts a prophylactic effect and that sphingosine-treated animals exhibit a strong survival advantage after infection. Furthermore, mechanistic studies showed that treatment with sphingosine leads to the early depolarization of the mitochondrial membrane potential (Δψm) and the generation of mitochondrial reactive oxygen species and to a release of cytochrome C within minutes, thereby presumably initiating apoptosis. Because of its very good tolerability and ease of application, inhaled sphingosine should be further developed as a possible prophylactic agent against pulmonary aspergillosis among severely immunocompromised patients. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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20 pages, 6598 KiB

Open AccessArticle

Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling

by Jiwang Chen, Angelia Lockett, Shuangping Zhao, Long Shuang Huang, Yifan Wang, Weiwen Wu, Ming Tang, Shahzaib Haider, Daniela Velez Rendon, Raheel Khan, Bing Liu, Nicholas Felesena, Justin R. Sysol, Daniela Valdez-Jasso, Haiyang Tang, Yang Bai, Viswanathan Natarajan and Roberto F. Machado

Int. J. Mol. Sci. 2022, 23(23), 14516; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314516 - 22 Nov 2022

Cited by 3 | Viewed by 2071

Abstract

Sphingosine kinase 1 (SPHK1) and the sphingosine-1-phosphate (S1P) signaling pathway have been shown to play a role in pulmonary arterial hypertension (PAH). S1P is an important stimulus for pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary vascular remodeling. We aimed to examine the specific roles of SPHK1 in PASMCs during pulmonary hypertension (PH) progression. We generated smooth muscle cell-specific, Sphk1-deficient (Sphk1^f/f TaglnCre⁺) mice and isolated Sphk1-deficient PASMCs from SPHK1 knockout mice. We demonstrated that Sphk1^f/f TaglnCre⁺ mice are protected from hypoxia or hypoxia/Sugen-mediated PH, and pulmonary vascular remodeling and that Sphk1-deficient PASMCs are less proliferative compared with ones isolated from wild-type (WT) siblings. S1P or hypoxia activated yes-associated protein 1 (YAP1) signaling by enhancing its translocation to the nucleus, which was dependent on SPHK1 enzymatic activity. Further, verteporfin, a pharmacologic YAP1 inhibitor, attenuated the S1P-mediated proliferation of hPASMCs, hypoxia-mediated PH, and pulmonary vascular remodeling in mice and hypoxia/Sugen-mediated severe PH in rats. Smooth muscle cell-specific SPHK1 plays an essential role in PH via YAP1 signaling, and YAP1 inhibition may have therapeutic potential in treating PH. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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17 pages, 6511 KiB

Open AccessArticle

β-Galactosylceramidase Deficiency Causes Upregulation of Long Pentraxin-3 in the Central Nervous System of Krabbe Patients and Twitcher Mice

by Daniela Coltrini, Adwaid Manu Krishna Chandran, Mirella Belleri, Pietro L. Poliani, Manuela Cominelli, Francesca Pagani, Miriam Capra, Stefano Calza, Simona Prioni, Laura Mauri, Alessandro Prinetti, Julia K. Kofler, Maria L. Escolar and Marco Presta

Int. J. Mol. Sci. 2022, 23(16), 9436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169436 - 21 Aug 2022

Cited by 3 | Viewed by 2630

Abstract

Globoid cell leukodystrophy (GLD), or Krabbe disease, is a neurodegenerative sphingolipidosis caused by genetic deficiency of lysosomal β-galactosylceramidase (GALC), characterized by neuroinflammation and demyelination of the central (CNS) and peripheral nervous system. The acute phase protein long pentraxin-3 (PTX3) is a soluble pattern recognition receptor and a regulator of innate immunity. Growing evidence points to the involvement of PTX3 in neurodegeneration. However, the expression and role of PTX3 in the neurodegenerative/neuroinflammatory processes that characterize GLD remain unexplored. Here, immunohistochemical analysis of brain samples from Krabbe patients showed that macrophages and globoid cells are intensely immunoreactive for PTX3. Accordingly, Ptx3 expression increases throughout the course of the disease in the cerebrum, cerebellum, and spinal cord of GALC-deficient twitcher (Galc^twi/twi) mice, an authentic animal model of GLD. This was paralleled by the upregulation of proinflammatory genes and M1-polarized macrophage/microglia markers and of the levels of PTX3 protein in CNS and plasma of twitcher animals. Crossing of Galc^twi/twi mice with transgenic PTX3 overexpressing animals (hPTX3 mice) demonstrated that constitutive PTX3 overexpression reduced the severity of clinical signs and the upregulation of proinflammatory genes in the spinal cord of P35 hPTX3/Galc^twi/twi mice when compared to Galc^twi/twi littermates, leading to a limited increase of their life span. However, this occurred in the absence of a significant impact on the histopathological findings and on the accumulation of the neurotoxic metabolite psychosine when evaluated at this late time point of the disease. In conclusion, our results provide the first evidence that PTX3 is produced in the CNS of GALC-deficient Krabbe patients and twitcher mice. PTX3 may exert a protective role by reducing the neuroinflammatory response that occurs in the spinal cord of GALC-deficient animals. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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15 pages, 3359 KiB

Open AccessArticle

Methuosis Contributes to Jaspine-B-Induced Cell Death

by Núria Bielsa, Mireia Casasampere, Jose Luis Abad, Carlos Enrich, Antonio Delgado, Gemma Fabriàs, Jose M. Lizcano and Josefina Casas

Int. J. Mol. Sci. 2022, 23(13), 7257; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137257 - 29 Jun 2022

Cited by 3 | Viewed by 2815

Abstract

Methuosis is a type of programmed cell death in which the cytoplasm is occupied by fluid-filled vacuoles that originate from macropinosomes (cytoplasmic vacuolation). A few molecules have been reported to behave as methuosis inducers in cancer cell lines. Jaspine B (JB) is a natural anhydrous sphingolipid (SL) derivative reported to induce cytoplasmic vacuolation and cytotoxicity in several cancer cell lines. Here, we have investigated the mechanism and signalling pathways involved in the cytotoxicity induced by the natural sphingolipid Jaspine B (JB) in lung adenocarcinoma A549 cells, which harbor the G12S K-Ras mutant. The effect of JB on inducing cytoplasmic vacuolation and modifying cell viability was determined in A549 cells, as well as in mouse embryonic fibroblasts (MEF) lacking either the autophagy-related gene ATG5 or BAX/BAK genes. Apoptosis was analyzed by flow cytometry after annexin V/propidium iodide staining, in the presence and absence of z-VAD. Autophagy was monitored by LC3-II/GFP-LC3-II analysis, and autophagic flux experiments using protease inhibitors. Phase contrast, confocal, and transmission electron microscopy were used to monitor cytoplasmic vacuolation and the uptake of Lucifer yellow to assess macropinocyosis. We present evidence that cytoplasmic vacuolation and methuosis are involved in Jaspine B cytotoxicity over A549 cells and that activation of 5′ AMP-activated protein kinase (AMPK) could be involved in Jaspine-B-induced vacuolation, independently of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 1 (PI3K/Akt/mTORC1) axis. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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14 pages, 2376 KiB

Open AccessArticle

Diesel Particulate Extract Accelerates Premature Skin Aging in Human Fibroblasts via Ceramide-1-Phosphate-Mediated Signaling Pathway

by Kyong-Oh Shin, Yoshikazu Uchida and Kyungho Park

Int. J. Mol. Sci. 2022, 23(5), 2691; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052691 - 28 Feb 2022

Cited by 9 | Viewed by 2385

Abstract

Both intrinsic (i.e., an individual’s body clock) and extrinsic factors (i.e., air pollutants and ultraviolet irradiation) accelerate premature aging. Epidemiological studies have shown a correlation between pollutant levels and aging skin symptoms. Diesel particle matter in particular leads to some diseases, including in the skin. Our recent study demonstrates that diesel particulate extract (DPE) increases apoptosis via increases in an anti-mitogenic/pro-apoptotic lipid mediator, ceramide in epidermal keratinocytes. Here, we investigated whether and how DPE accelerates premature skin aging using cultured normal human dermal fibroblasts (HDF). We first demonstrated that DPE increases cell senescence marker β-galactosidase activity in HDF. We then found increases in mRNA and protein levels, along with activity of matrix metalloprotease (MMP)-1 and MMP-3, which are associated with skin aging following DPE exposure. We confirmed increases in collagen degradation in HDF treated with DPE. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is activated by DPE and results in increased ceramide production by sphingomyelinase activation in HDF. We identified that ceramide-1-phosphate (C1P) (produced from ceramide by ceramide kinase activation) activates MMP-1 and MMP-3 through activation of arachidonate cascade, followed by STAT 1- and STAT 3-dependent transcriptional activation. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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17 pages, 2527 KiB

Open AccessCommunication

Therapeutic CFTR Correction Normalizes Systemic and Lung-Specific S1P Level Alterations Associated with Heart Failure

by Franziska E. Uhl, Lotte Vanherle, Frank Matthes and Anja Meissner

Int. J. Mol. Sci. 2022, 23(2), 866; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020866 - 14 Jan 2022

Cited by 4 | Viewed by 1990

Abstract

Heart failure (HF) is among the main causes of death worldwide. Alterations of sphingosine-1-phosphate (S1P) signaling have been linked to HF as well as to target organ damage that is often associated with HF. S1P’s availability is controlled by the cystic fibrosis transmembrane regulator (CFTR), which acts as a critical bottleneck for intracellular S1P degradation. HF induces CFTR downregulation in cells, tissues and organs, including the lung. Whether CFTR alterations during HF also affect systemic and tissue-specific S1P concentrations has not been investigated. Here, we set out to study the relationship between S1P and CFTR expression in the HF lung. Mice with HF, induced by myocardial infarction, were treated with the CFTR corrector compound C18 starting ten weeks post-myocardial infarction for two consecutive weeks. CFTR expression, S1P concentrations, and immune cell frequencies were determined in vehicle- and C18-treated HF mice and sham controls using Western blotting, flow cytometry, mass spectrometry, and qPCR. HF led to decreased pulmonary CFTR expression, which was accompanied by elevated S1P concentrations and a pro-inflammatory state in the lungs. Systemically, HF associated with higher S1P plasma levels compared to sham-operated controls and presented with higher S1P receptor 1-positive immune cells in the spleen. CFTR correction with C18 attenuated the HF-associated alterations in pulmonary CFTR expression and, hence, led to lower pulmonary S1P levels, which was accompanied by reduced lung inflammation. Collectively, these data suggest an important role for the CFTR-S1P axis in HF-mediated systemic and pulmonary inflammation. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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15 pages, 2253 KiB

Open AccessArticle

Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer

by Mayuko Ikarashi, Junko Tsuchida, Masayuki Nagahashi, Shiho Takeuchi, Kazuki Moro, Chie Toshikawa, Shun Abe, Hiroshi Ichikawa, Yoshifumi Shimada, Jun Sakata, Yu Koyama, Nobuaki Sato, Nitai C. Hait, Yiwei Ling, Shujiro Okuda, Kazuaki Takabe and Toshifumi Wakai

Int. J. Mol. Sci. 2021, 22(24), 13367; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413367 - 13 Dec 2021

Cited by 7 | Viewed by 2706

Abstract

Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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16 pages, 2136 KiB

Open AccessArticle

Time-Dependent Changes in Hepatic Sphingolipid Accumulation and PI3K/Akt/mTOR Signaling Pathway in a Rat Model of NAFLD

by Klaudia Sztolsztener, Karolina Konstantynowicz-Nowicka, Ewa Harasim-Symbor and Adrian Chabowski

Int. J. Mol. Sci. 2021, 22(22), 12478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212478 - 19 Nov 2021

Cited by 10 | Viewed by 2004

Abstract

Increased lipid bioavailability in a diet favors lipid accumulation, enhancing hepatic lipotoxicity and contributing to insulin resistance (IR) development. The aim of our study was to examine time-dependent alterations in the intrahepatic content of sphingolipids and insulin signaling pathway in rats fed a high-fat diet (HFD). The experiment was conducted on male Wistar rats receiving a standard diet or HFD for five weeks. At the end of each experimental feeding week, liver sphingolipids were determined using high-performance liquid chromatography. The expression of proteins from the sphingolipid pathway and glucose transporter expression were assessed by Western blot. The content of phosphorylated form of proteins from the insulin pathway was detected by a multiplex assay kit. Our results revealed that HFD enhanced hepatic ceramide deposition by increasing the expression of selected proteins from sphingomyelin and salvage pathways in the last two weeks. Importantly, we observed a significant inhibition of Akt phosphorylation in the first week of HFD and stimulation of PTEN and mTOR phosphorylation at the end of HFD. These changes worsened the PI3K/Akt/mTOR signaling pathway. We may postulate that HFD-induced reduction in the insulin action in the time-dependent matter was exerted by excessive accumulation of sphingosine and sphinganine rather than ceramide. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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18 pages, 1986 KiB

Open AccessArticle

Sphingosine-1 Phosphate Lyase Regulates Sensitivity of Pancreatic Beta-Cells to Lipotoxicity

by Yadi Tang, Thomas Plötz, Markus H. Gräler and Ewa Gurgul-Convey

Int. J. Mol. Sci. 2021, 22(19), 10893; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910893 - 08 Oct 2021

Cited by 3 | Viewed by 2036

Abstract

Elevated levels of free fatty acids (FFAs) have been related to pancreatic beta-cell failure in type 2 diabetes (T2DM), though the underlying mechanisms are not yet fully understood. FFAs have been shown to dysregulate formation of bioactive sphingolipids, such as ceramides and sphingosine-1 phosphate (S1P) in beta-cells. The aim of this study was to analyze the role of sphingosine-1 phosphate lyase (SPL), a key enzyme of the sphingolipid pathway that catalyzes an irreversible degradation of S1P, in the sensitivity of beta-cells to lipotoxicity. To validate the role of SPL in lipotoxicity, we modulated SPL expression in rat INS1E cells and in human EndoC-βH1 beta-cells. SPL overexpression in INS1E cells (INS1E-SPL), which are characterized by a moderate basal expression level of SPL, resulted in an acceleration of palmitate-mediated cell viability loss, proliferation inhibition and induction of oxidative stress. SPL overexpression affected the mRNA expression of ER stress markers and mitochondrial chaperones. In contrast to control cells, in INS1E-SPL cells no protective effect of oleate was detected. Moreover, Plin2 expression and lipid droplet formation were strongly reduced in OA-treated INS1E-SPL cells. Silencing of SPL in human EndoC-βH1 beta-cells, which are characterized by a significantly higher SPL expression as compared to rodent beta-cells, resulted in prevention of FFA-mediated caspase-3/7 activation. Our findings indicate that an adequate control of S1P degradation by SPL might be crucially involved in the susceptibility of pancreatic beta-cells to lipotoxicity. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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Review

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38 pages, 2279 KiB

Open AccessReview

Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies

by Yasharah Raza, Jane Atallah and Chiara Luberto

Int. J. Mol. Sci. 2022, 23(21), 12745; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112745 - 22 Oct 2022

Cited by 1 | Viewed by 2048

Abstract

Dysregulation of sphingolipid metabolism plays a complex role in hematological malignancies, beginning with the first historical link between sphingolipids and apoptosis discovered in HL-60 leukemic cells. Numerous manuscripts have reviewed the field including the early discoveries that jumpstarted the studies. Many studies discussed here support a role for sphingolipids, such as ceramide, in combinatorial therapeutic regimens to enhance anti-leukemic effects and reduce resistance to standard therapies. Additionally, inhibitors of specific nodes of the sphingolipid pathway, such as sphingosine kinase inhibitors, significantly reduce leukemic cell survival in various types of leukemias. Acid ceramidase inhibitors have also shown promising results in acute myeloid leukemia. As the field moves rapidly, here we aim to expand the body of literature discussed in previously published reviews by focusing on advances reported in the latter part of the last decade. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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14 pages, 927 KiB

Open AccessReview

Emerging Roles of Ceramides in Breast Cancer Biology and Therapy

by Purab Pal, G. Ekin Atilla-Gokcumen and Jonna Frasor

Int. J. Mol. Sci. 2022, 23(19), 11178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911178 - 23 Sep 2022

Cited by 11 | Viewed by 2982

Abstract

One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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31 pages, 2858 KiB

Open AccessReview

Targeting the Sphingolipid Rheostat in Gliomas

by Faris Zaibaq, Tyrone Dowdy and Mioara Larion

Int. J. Mol. Sci. 2022, 23(16), 9255; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169255 - 17 Aug 2022

Cited by 6 | Viewed by 3103

Abstract

Gliomas are highly aggressive cancer types that are in urgent need of novel drugs and targeted therapies. Treatment protocols have not improved in over a decade, and glioma patient survival remains among the worst of all cancer types. As a result, cancer metabolism research has served as an innovative approach to identifying novel glioma targets and improving our understanding of brain tumors. Recent research has uncovered a unique metabolic vulnerability in the sphingolipid pathways of gliomas that possess the IDH1 mutation. Sphingolipids are a family of lipid signaling molecules that play a variety of second messenger functions in cellular regulation. The two primary metabolites, sphingosine-1-phosphate (S1P) and ceramide, maintain a rheostat balance and play opposing roles in cell survival and proliferation. Altering the rheostat such that the pro-apoptotic signaling of the ceramides outweighs the pro-survival S1P signaling in glioma cells diminishes the hallmarks of cancer and enhances tumor cell death. Throughout this review, we discuss the sphingolipid pathway and identify the enzymes that can be most effectively targeted to alter the sphingolipid rheostat and enhance apoptosis in gliomas. We discuss each pathway’s steps based on their site of occurrence in the organelles and postulate novel targets that can effectively exploit this vulnerability. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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16 pages, 1516 KiB

Open AccessReview

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

by Cristina Tringali and Paola Giussani

Int. J. Mol. Sci. 2022, 23(14), 7806; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147806 - 15 Jul 2022

Cited by 8 | Viewed by 2145

Abstract

Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies. Full article

(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases 2.0)

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