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15 pages, 1993 KiB

Open AccessArticle

Ursodeoxycholic Acid Binds PERK and Ameliorates Neurite Atrophy in a Cellular Model of GM2 Gangliosidosis

by Carolina Morales, Macarena Fernandez, Rodrigo Ferrer, Daniel Raimunda, Dolores C. Carrer and Mariana Bollo

Int. J. Mol. Sci. 2023, 24(8), 7209; https://doi.org/10.3390/ijms24087209 - 13 Apr 2023

Cited by 2 | Viewed by 1999

Abstract

The Unfolded protein response (UPR), triggered by stress in the endoplasmic reticulum (ER), is a key driver of neurodegenerative diseases. GM2 gangliosidosis, which includes Tay-Sachs and Sandhoff disease, is caused by an accumulation of GM2, mainly in the brain, that leads to progressive [...] Read more.

The Unfolded protein response (UPR), triggered by stress in the endoplasmic reticulum (ER), is a key driver of neurodegenerative diseases. GM2 gangliosidosis, which includes Tay-Sachs and Sandhoff disease, is caused by an accumulation of GM2, mainly in the brain, that leads to progressive neurodegeneration. Previously, we demonstrated in a cellular model of GM2 gangliosidosis that PERK, a UPR sensor, contributes to neuronal death. There is currently no approved treatment for these disorders. Chemical chaperones, such as ursodeoxycholic acid (UDCA), have been found to alleviate ER stress in cell and animal models. UDCA’s ability to move across the blood-brain barrier makes it interesting as a therapeutic tool. Here, we found that UDCA significantly diminished the neurite atrophy induced by GM2 accumulation in primary neuron cultures. It also decreased the up-regulation of pro-apoptotic CHOP, a downstream PERK-signaling component. To explore its potential mechanisms of action, in vitro kinase assays and crosslinking experiments were performed with different variants of recombinant protein PERK, either in solution or in reconstituted liposomes. The results suggest a direct interaction between UDCA and the cytosolic domain of PERK, which promotes kinase phosphorylation and dimerization. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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18 pages, 3418 KiB

Open AccessArticle

Neu3 Sialidase Activates the RISK Cardioprotective Signaling Pathway during Ischemia and Reperfusion Injury (IRI)

by Marco Piccoli, Simona Coviello, Maria Elena Canali, Paola Rota, Paolo La Rocca, Federica Cirillo, Ivana Lavota, Adriana Tarantino, Giuseppe Ciconte, Carlo Pappone, Andrea Ghiroldi and Luigi Anastasia

Int. J. Mol. Sci. 2022, 23(11), 6090; https://doi.org/10.3390/ijms23116090 - 29 May 2022

Cited by 2 | Viewed by 2246

Abstract

Coronary reperfusion strategies are life-saving approaches to restore blood flow to cardiac tissue after acute myocardial infarction (AMI). However, the sudden restoration of normal blood flow leads to ischemia and reperfusion injury (IRI), which results in cardiomyoblast death, irreversible tissue degeneration, and heart [...] Read more.

Coronary reperfusion strategies are life-saving approaches to restore blood flow to cardiac tissue after acute myocardial infarction (AMI). However, the sudden restoration of normal blood flow leads to ischemia and reperfusion injury (IRI), which results in cardiomyoblast death, irreversible tissue degeneration, and heart failure. The molecular mechanism of IRI is not fully understood, and there are no effective cardioprotective strategies to prevent it. In this study, we show that activation of sialidase-3, a glycohydrolytic enzyme that cleaves sialic acid residues from glycoconjugates, is cardioprotective by triggering RISK pro-survival signaling pathways. We found that overexpression of Neu3 significantly increased cardiomyoblast resistance to IRI through activation of HIF-1α and Akt/Erk signaling pathways. This raises the possibility of using Sialidase-3 activation as a cardioprotective reperfusion strategy after myocardial infarction. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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20 pages, 3978 KiB

Open AccessArticle

Hyperosmotic Stress Induces Phosphorylation of CERT and Enhances Its Tethering throughout the Endoplasmic Reticulum

by Kentaro Shimasaki, Keigo Kumagai, Shota Sakai, Toshiyuki Yamaji and Kentaro Hanada

Int. J. Mol. Sci. 2022, 23(7), 4025; https://doi.org/10.3390/ijms23074025 - 5 Apr 2022

Cited by 4 | Viewed by 2233

Abstract

The ceramide transport protein (CERT) delivers ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus, where ceramide is converted to sphingomyelin (SM). The function of CERT is regulated in two distinct phosphorylation-dependent events: multiple phosphorylations in a serine-repeat motif (SRM) and phosphorylation [...] Read more.

The ceramide transport protein (CERT) delivers ceramide from the endoplasmic reticulum (ER) to the Golgi apparatus, where ceramide is converted to sphingomyelin (SM). The function of CERT is regulated in two distinct phosphorylation-dependent events: multiple phosphorylations in a serine-repeat motif (SRM) and phosphorylation of serine 315 residue (S315). Pharmacological inhibition of SM biosynthesis results in an increase in SRM-dephosphorylated CERT, which serves as an activated form, and an enhanced phosphorylation of S315, which augments the binding of CERT to ER-resident VAMP-associated protein (VAP), inducing the full activation of CERT to operate at the ER–Golgi membrane contact sites (MCSs). However, it remains unclear whether the two phosphorylation-dependent regulatory events always occur coordinately. Here, we describe that hyperosmotic stress induces S315 phosphorylation without affecting the SRM-phosphorylation state. Under hyperosmotic conditions, the binding of CERT with VAP-A is enhanced in an S315 phosphorylation-dependent manner, and this increased binding occurs throughout the ER rather than restrictedly at the ER–Golgi MCSs. Moreover, we found that de novo synthesis of SM with very-long acyl chains preferentially increases via a CERT-independent mechanism under hyperosmotic-stressed cells, providing an insight into a CERT-independent ceramide transport pathway for de novo synthesis of SM. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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16 pages, 4180 KiB

Open AccessArticle

Sphingosine 1-Phosphate Receptor 5 (S1P₅) Knockout Ameliorates Adenine-Induced Nephropathy

by Timon Eckes, Sammy Patyna, Alexander Koch, Anke Oftring, Stefan Gauer, Nicholas Obermüller, Stephanie Schwalm, Liliana Schaefer, Jerold Chun, Hermann-Josef Gröne and Josef Pfeilschifter

Int. J. Mol. Sci. 2022, 23(7), 3952; https://doi.org/10.3390/ijms23073952 - 2 Apr 2022

Cited by 3 | Viewed by 2501

Abstract

S1P and its receptors have been reported to play important roles in the development of renal fibrosis. Although S1P₅ has barely been investigated so far, there are indications that it can influence inflammatory and fibrotic processes. Here, we report the role of [...] Read more.

S1P and its receptors have been reported to play important roles in the development of renal fibrosis. Although S1P₅ has barely been investigated so far, there are indications that it can influence inflammatory and fibrotic processes. Here, we report the role of S1P₅ in renal inflammation and fibrosis. Male S1P₅ knockout mice and wild-type mice on a C57BL/6J background were fed with an adenine-rich diet for 7 days or 14 days to induce tubulointerstitial fibrosis. The kidneys of untreated mice served as respective controls. Kidney damage, fibrosis, and inflammation in kidney tissues were analyzed by real-time PCR, Western blot, and histological staining. Renal function was assessed by plasma creatinine ELISA. The S1P₅ knockout mice had better renal function and showed less kidney damage, less proinflammatory cytokine release, and less fibrosis after 7 days and 14 days of an adenine-rich diet compared to wild-type mice. S1P₅ knockout ameliorates tubular damage and tubulointerstitial fibrosis in a model of adenine-induced nephropathy in mice. Thus, targeting S1P₅ might be a promising goal for the pharmacological treatment of kidney diseases. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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16 pages, 2777 KiB

Open AccessArticle

In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P₁) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P₁ Receptor Modulator

by Lisa Schlicher, Paulina Kulig, Audrey von Münchow, Mark J. Murphy and Marcel P. Keller

Int. J. Mol. Sci. 2022, 23(3), 1191; https://doi.org/10.3390/ijms23031191 - 21 Jan 2022

Cited by 3 | Viewed by 3196

Abstract

Cenerimod is a potent, selective sphingosine 1-phosphate receptor 1 (S1P₁) modulator currently investigated in a Phase IIb study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P₁ receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells [...] Read more.

Cenerimod is a potent, selective sphingosine 1-phosphate receptor 1 (S1P₁) modulator currently investigated in a Phase IIb study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P₁ receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including T and B lymphocytes) in the bloodstream and inflamed tissues, making them an effective therapeutic concept for autoimmune disorders. Although the effect of S1P receptor modulators in reducing circulating lymphocytes is well documented, the precise molecular role of the S1P₁ receptor on these cell types is not fully understood. In this study, the mode of action of cenerimod on human primary lymphocytes in different activation states was investigated focusing on their chemotactic behavior towards S1P in real-time, concomitant to S1P₁ receptor expression and internalization dynamics. Here, we show that cenerimod effectively prevents T and B cell migration in a concentration-dependent manner. Interestingly, while T cell activation led to strong S1P₁ re-expression and enhanced migration; in B cells, an enhanced migration capacity and S1P₁ receptor surface expression was observed in an unstimulated state. Importantly, concomitant treatment with glucocorticoids (GCs), a frequently used treatment for autoimmune disorders, had no impact on the inhibitory activity of cenerimod on lymphocytes. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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17 pages, 2252 KiB

Open AccessArticle

Plasma Membrane Calcium ATPase-Neuroplastin Complexes Are Selectively Stabilized in GM1-Containing Lipid Rafts

by Katarina Ilic, Xiao Lin, Ayse Malci, Mario Stojanović, Borna Puljko, Marko Rožman, Željka Vukelić, Marija Heffer, Dirk Montag, Ronald L. Schnaar, Svjetlana Kalanj-Bognar, Rodrigo Herrera-Molina and Kristina Mlinac-Jerkovic

Int. J. Mol. Sci. 2021, 22(24), 13590; https://doi.org/10.3390/ijms222413590 - 18 Dec 2021

Cited by 12 | Viewed by 4199

Abstract

The recent identification of plasma membrane (Ca²⁺)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the hypothesis that PMCA-Neuroplastin complexes exist in specific ganglioside-containing rafts, which [...] Read more.

The recent identification of plasma membrane (Ca²⁺)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the hypothesis that PMCA-Neuroplastin complexes exist in specific ganglioside-containing rafts, which could affect calcium homeostasis. We analyzed the abundance of all four PMCA paralogs (PMCA1-4) and Neuroplastin isoforms (Np65 and Np55) in lipid rafts and bulk membrane fractions from GM2/GD2 synthase-deficient mouse brains. In these fractions, we found altered distribution of Np65/Np55 and selected PMCA isoforms, namely PMCA1 and 2. Cell surface staining and confocal microscopy identified GM1 as the main complex ganglioside co-localizing with Neuroplastin in cultured hippocampal neurons. Furthermore, blocking GM1 with a specific antibody resulted in delayed calcium restoration of electrically evoked calcium transients in the soma of hippocampal neurons. The content and composition of all ganglioside species were unchanged in Neuroplastin-deficient mouse brains. Therefore, we conclude that altered composition or disorganization of ganglioside-containing rafts results in changed regulation of calcium signals in neurons. We propose that GM1 could be a key sphingolipid for ensuring proper location of the PMCA-Neuroplastin complexes into rafts in order to participate in the regulation of neuronal calcium homeostasis. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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23 pages, 7578 KiB

Open AccessArticle

The Potential Role of Human NME1 in Neuronal Differentiation of Porcine Mesenchymal Stem Cells: Application of NB-hNME1 as a Human NME1 Suppressor

by Jin Hyoung Cho, Won Seok Ju, Sang Young Seo, Bo Hyun Kim, Ji-Su Kim, Jong-Geol Kim, Soon Ju Park and Young-Kug Choo

Int. J. Mol. Sci. 2021, 22(22), 12194; https://doi.org/10.3390/ijms222212194 - 11 Nov 2021

Cited by 3 | Viewed by 2601

Abstract

This study aimed to investigate the effects of the human macrophage (MP) secretome in cellular xenograft rejection. The role of human nucleoside diphosphate kinase A (hNME1), from the secretome of MPs involved in the neuronal differentiation of miniature pig adipose tissue-derived mesenchymal stem [...] Read more.

This study aimed to investigate the effects of the human macrophage (MP) secretome in cellular xenograft rejection. The role of human nucleoside diphosphate kinase A (hNME1), from the secretome of MPs involved in the neuronal differentiation of miniature pig adipose tissue-derived mesenchymal stem cells (mp AD-MSCs), was evaluated by proteomic analysis. Herein, we first demonstrate that hNME1 strongly binds to porcine ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 (pST8SIA1), which is a ganglioside GD3 synthase. When hNME1 binds with pST8SIA1, it induces degradation of pST8SIA1 in mp AD-MSCs, thereby inhibiting the expression of ganglioside GD3 followed by decreased neuronal differentiation of mp AD-MSCs. Therefore, we produced nanobodies (NBs) named NB-hNME1 that bind to hNME1 specifically, and the inhibitory effect of NB-hNME1 was evaluated for blocking the binding between hNME1 and pST8SIA1. Consequently, NB-hNME1 effectively blocked the binding of hNME1 to pST8SIA1, thereby recovering the expression of ganglioside GD3 and neuronal differentiation of mp AD-MSCs. Our findings suggest that mp AD-MSCs could be a potential candidate for use as an additive, such as an immunosuppressant, in stem cell transplantation. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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17 pages, 5956 KiB

Open AccessArticle

α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes

by Ulrich Jehn, Samet Bayraktar, Solvey Pollmann, Veerle Van Marck, Thomas Weide, Hermann Pavenstädt, Eva Brand and Malte Lenders

Int. J. Mol. Sci. 2021, 22(21), 11339; https://doi.org/10.3390/ijms222111339 - 20 Oct 2021

Cited by 16 | Viewed by 3570

Abstract

Fabry disease (FD) is caused by mutations in the α-galactosidase A (GLA) gene encoding the lysosomal AGAL enzyme. Loss of enzymatic AGAL activity and cellular accumulation of sphingolipids (mainly globotriaosylcermide) may lead to podocyturia and renal loss of function with increased [...] Read more.

Fabry disease (FD) is caused by mutations in the α-galactosidase A (GLA) gene encoding the lysosomal AGAL enzyme. Loss of enzymatic AGAL activity and cellular accumulation of sphingolipids (mainly globotriaosylcermide) may lead to podocyturia and renal loss of function with increased cardiovascular morbidity and mortality in affected patients. To identify dysregulated cellular pathways in FD, we established a stable AGAL-deficient podocyte cell line to perform a comprehensive proteome analysis. Imbalanced protein expression and function were analyzed in additional FD cell lines including endothelial, epithelial kidney, patient-derived urinary cells and kidney biopsies. AGAL-deficient podocytes showed dysregulated proteins involved in thermogenesis, lysosomal trafficking and function, metabolic activity, cell-cell interactions and cell cycle. Proteins associated with neurological diseases were upregulated in AGAL-deficient podocytes. Rescues with inducible AGAL expression only partially normalized protein expression. A disturbed protein expression was confirmed in endothelial, epithelial and patient-specific cells, pointing toward fundamental pathway disturbances rather than to cell type-specific alterations in FD. We conclude that a loss of AGAL function results in profound changes of cellular pathways, which are ubiquitously in different cell types. Due to these profound alterations, current approved FD-specific therapies may not be sufficient to completely reverse all dysregulated pathways. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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22 pages, 12419 KiB

Open AccessArticle

Mouse Liver Compensates Loss of Sgpl1 by Secretion of Sphingolipids into Blood and Bile

by Anna Katharina Spohner, Katja Jakobi, Sandra Trautmann, Dominique Thomas, Fabian Schumacher, Burkhard Kleuser, Dieter Lütjohann, Khadija El-Hindi, Sabine Grösch, Josef Pfeilschifter, Julie D. Saba and Dagmar Meyer zu Heringdorf

Int. J. Mol. Sci. 2021, 22(19), 10617; https://doi.org/10.3390/ijms221910617 - 30 Sep 2021

Cited by 5 | Viewed by 2673

Abstract

Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role [...] Read more.

Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1^HepKO mice). Sgpl1^HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5–2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1^HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewhere. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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22 pages, 10158 KiB

Open AccessArticle

Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature

by Enrica Torretta, Micaela Garziano, Mariacristina Poliseno, Daniele Capitanio, Mara Biasin, Teresa Antonia Santantonio, Mario Clerici, Sergio Lo Caputo, Daria Trabattoni and Cecilia Gelfi

Int. J. Mol. Sci. 2021, 22(19), 10198; https://doi.org/10.3390/ijms221910198 - 22 Sep 2021

Cited by 43 | Viewed by 3602

Abstract

The reason behind the high inter-individual variability in response to SARS-CoV-2 infection and patient’s outcome is poorly understood. The present study targets the sphingolipid profile of twenty-four healthy controls and fifty-nine COVID-19 patients with different disease severity. Sera were analyzed by untargeted and [...] Read more.

The reason behind the high inter-individual variability in response to SARS-CoV-2 infection and patient’s outcome is poorly understood. The present study targets the sphingolipid profile of twenty-four healthy controls and fifty-nine COVID-19 patients with different disease severity. Sera were analyzed by untargeted and targeted mass spectrometry and ELISA. Results indicated a progressive increase in dihydrosphingosine, dihydroceramides, ceramides, sphingosine, and a decrease in sphingosine-1-phosphate. These changes are associated with a serine palmitoyltransferase long chain base subunit 1 (SPTLC1) increase in relation to COVID-19 severity. Severe patients showed a decrease in sphingomyelins and a high level of acid sphingomyelinase (aSMase) that influences monosialodihexosyl ganglioside (GM3) C16:0 levels. Critical patients are characterized by high levels of dihydrosphingosine and dihydroceramide but not of glycosphingolipids. In severe and critical patients, unbalanced lipid metabolism induces lipid raft remodeling, leads to cell apoptosis and immunoescape, suggesting active sphingolipid participation in viral infection. Furthermore, results indicated that the sphingolipid and glycosphingolipid metabolic rewiring promoted by aSMase and GM3 is age-dependent but also characteristic of severe and critical patients influencing prognosis and increasing viral load. AUCs calculated from ROC curves indicated ceramides C16:0, C18:0, C24:1, sphingosine and SPTLC1 as putative biomarkers of disease evolution. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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16 pages, 4914 KiB

Open AccessArticle

Antagonizing S1P₃ Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

by Angela Corvino, Ida Cerqua, Alessandra Lo Bianco, Giuseppe Caliendo, Ferdinando Fiorino, Francesco Frecentese, Elisa Magli, Elena Morelli, Elisa Perissutti, Vincenzo Santagada, Giuseppe Cirino, Elisabetta Granato, Fiorentina Roviezzo, Elisa Puliti, Caterina Bernacchioni, Antonio Lavecchia, Chiara Donati and Beatrice Severino

Int. J. Mol. Sci. 2021, 22(16), 8861; https://doi.org/10.3390/ijms22168861 - 17 Aug 2021

Cited by 2 | Viewed by 2218

Abstract

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P_1-5). Increasing numbers of studies have indicated the importance of S1P₃ in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as [...] Read more.

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P_1-5). Increasing numbers of studies have indicated the importance of S1P₃ in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P₃ receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P₃ selective pepducin agonist) and KRX-722 (an S1P₁-selective pepducin agonist). Those selective towards S1P₃ (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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19 pages, 5375 KiB

Open AccessArticle

Glycosphingolipids with Very Long-Chain Fatty Acids Accumulate in Fibroblasts from Adrenoleukodystrophy Patients

by Yuko Fujiwara, Kotaro Hama, Nobuyuki Shimozawa and Kazuaki Yokoyama

Int. J. Mol. Sci. 2021, 22(16), 8645; https://doi.org/10.3390/ijms22168645 - 11 Aug 2021

Cited by 9 | Viewed by 2433

Abstract

Adrenoleukodystrophy (X-ALD) is an X-linked genetic disorder caused by mutation of the ATP-binding cassette subfamily D member 1 gene, which encodes the peroxisomal membrane protein, adrenoleukodystrophy protein (ALDP). ALDP is associated with the transport of very-long-chain fatty acids (VLCFAs; carbon chain length ≥ [...] Read more.

Adrenoleukodystrophy (X-ALD) is an X-linked genetic disorder caused by mutation of the ATP-binding cassette subfamily D member 1 gene, which encodes the peroxisomal membrane protein, adrenoleukodystrophy protein (ALDP). ALDP is associated with the transport of very-long-chain fatty acids (VLCFAs; carbon chain length ≥ 24) into peroxisomes. Defective ALDP leads to the accumulation of saturated VLCFAs in plasma and tissues, which results in damage to myelin and the adrenal glands. Here, we profiled the glycosphingolipid (GSL) species in fibroblasts from X-ALD patients. Quantitative analysis was performed using liquid chromatography–electrospray ionization–tandem mass spectrometry with a chiral column in multiple reaction monitoring (MRM) mode. MRM transitions were designed to scan for precursor ions of long-chain bases to detect GSLs, neutral loss of hexose to detect hexosylceramide (HexCer), and precursor ions of phosphorylcholine to detect sphingomyelin (SM). Our results reveal that levels of C25 and C26-containing HexCer, Hex2Cer, NeuAc-Hex2Cer, NeuAc-HexNAc-Hex2Cer, Hex3Cer, HexNAc-Hex3Cer, and SM were elevated in fibroblasts from X-ALD patients. In conclusion, we precisely quantified SM and various GSLs in fibroblasts from X-ALD patients and determined structural information of the elevated VLCFA-containing GSLs. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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20 pages, 38099 KiB

Open AccessArticle

Characterization of Glycosphingolipids in the Human Parathyroid and Thyroid Glands

by Karin Säljö, Anders Thornell, Chunsheng Jin, Peter Stålberg, Olov Norlén and Susann Teneberg

Int. J. Mol. Sci. 2021, 22(13), 7044; https://doi.org/10.3390/ijms22137044 - 30 Jun 2021

Cited by 5 | Viewed by 2742

Abstract

As part of a systematic investigation of the glycosphingolipids in human tissues, acid and non-acid glycosphingolipids from human thyroid and parathyroid glands were isolated and characterized with mass spectrometry and binding of carbohydrate-recognizing ligands, with a focus on complex compounds. The glycosphingolipid patterns [...] Read more.

As part of a systematic investigation of the glycosphingolipids in human tissues, acid and non-acid glycosphingolipids from human thyroid and parathyroid glands were isolated and characterized with mass spectrometry and binding of carbohydrate-recognizing ligands, with a focus on complex compounds. The glycosphingolipid patterns of the human parathyroid and thyroid glands were very similar. The major acid glycosphingolipids were sulfatide and the gangliosides GM3, GD3, GD1a, GD1b, GT1b and Neu5Ac-neolactotetraosylceramide, and the major non-acid glycosphingolipids were globotriaosylceramide and globoside. We also found neolactotetra- and neolactohexaosylceramide, the x₂ glycosphingolipid, and complex glycosphingolipids with terminal blood group O and A determinants in both tissues. A glycosphingolipid with blood group Le^b determinant was identified in the thyroid gland, and the parathyroid sample had a glycosphingolipid with terminal blood group B determinant. Immunohistochemistry demonstrated the expression of blood group A antigens in both the thyroid and parathyroid glands. A weak cytoplasmatic expression of the GD1a ganglioside was present in the thyroid, while the parathyroid gland had a strong GD1a expression on the cell surface. Thus, the glycosylation of human thyroid and parathyroid glands is more complex than previously appreciated. Our findings provide a platform for further studies of alterations of cell surface glycosphingolipids in thyroid and parathyroid cancers. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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14 pages, 1309 KiB

Open AccessArticle

mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment

by Cosima Rhein, Iulia Zoicas, Lena M. Marx, Stefanie Zeitler, Tobias Hepp, Claudia von Zimmermann, Christiane Mühle, Tanja Richter-Schmidinger, Bernd Lenz, Yesim Erim, Martin Reichel, Erich Gulbins and Johannes Kornhuber

Int. J. Mol. Sci. 2021, 22(11), 5700; https://doi.org/10.3390/ijms22115700 - 27 May 2021

Cited by 9 | Viewed by 3515

Abstract

Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes [...] Read more.

Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of SMPD1, which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, Smpd1 mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that SMPD1 mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that SMPD1 mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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18 pages, 2921 KiB

Open AccessArticle

Identification of SYS1 as a Host Factor Required for Shiga Toxin-Mediated Cytotoxicity in Vero Cells

by Chisato Sakuma, Tsuyoshi Sekizuka, Makoto Kuroda, Kentaro Hanada and Toshiyuki Yamaji

Int. J. Mol. Sci. 2021, 22(9), 4936; https://doi.org/10.3390/ijms22094936 - 6 May 2021

Cited by 5 | Viewed by 3039

Abstract

Shiga toxin (STx) or Vero toxin is a virulence factor produced by enterohemorrhagic Escherichia coli. The toxin binds to the glycosphingolipid globotriaosylceramide (Gb3) for its entry, and causes cell death by inhibiting ribosome function. Previously, we performed a loss-of-function screen in HeLa [...] Read more.

Shiga toxin (STx) or Vero toxin is a virulence factor produced by enterohemorrhagic Escherichia coli. The toxin binds to the glycosphingolipid globotriaosylceramide (Gb3) for its entry, and causes cell death by inhibiting ribosome function. Previously, we performed a loss-of-function screen in HeLa cells using a human CRISPR knockout (KO) library and identified various host genes required for STx-induced cell death. To determine whether this library targeted to the human genome is applicable to non-human primate cells and to identify previously unrecognized factors crucial for STx-induced cell death, we herein performed a similar screen in the African green monkey kidney-derived Vero C1008 subline. Many genes relevant to metabolic enzymes and membrane trafficking were enriched, although the number of enriched genes was less than that obtained in the screening for HeLa cells. Of note, several genes that had not been enriched in the previous screening were enriched: one of these genes was SYS1, which encodes a multi-spanning membrane protein in the Golgi apparatus. In SYS1 KO Vero cells, expression of Gb3 and sphingomyelin was decreased, while that of glucosylceramide and lactosylceramide was increased. In addition, loss of SYS1 inhibited the biosynthesis of protein glycans, deformed the Golgi apparatus, and perturbed the localization of trans-Golgi network protein (TGN) 46. These results indicate that the human CRISPR KO library is applicable to Vero cell lines, and SYS1 has a widespread effect on glycan biosynthesis via regulation of intra-Golgi and endosome–TGN retrograde transports. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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21 pages, 1125 KiB

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To Be or Not to Be: The Divergent Action and Metabolism of Sphingosine-1 Phosphate in Pancreatic Beta-Cells in Response to Cytokines and Fatty Acids

by Ewa Gurgul-Convey

Int. J. Mol. Sci. 2022, 23(3), 1638; https://doi.org/10.3390/ijms23031638 - 31 Jan 2022

Cited by 7 | Viewed by 2987

Abstract

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with multiple functions conveyed by the activation of cell surface receptors and/or intracellular mediators. A growing body of evidence indicates its important role in pancreatic insulin-secreting beta-cells that are necessary for maintenance of glucose homeostasis. The [...] Read more.

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with multiple functions conveyed by the activation of cell surface receptors and/or intracellular mediators. A growing body of evidence indicates its important role in pancreatic insulin-secreting beta-cells that are necessary for maintenance of glucose homeostasis. The dysfunction and/or death of beta-cells lead to diabetes development. Diabetes is a serious public health burden with incidence growing rapidly in recent decades. The two major types of diabetes are the autoimmune-mediated type 1 diabetes (T1DM) and the metabolic stress-related type 2 diabetes (T2DM). Despite many differences in the development, both types of diabetes are characterized by chronic hyperglycemia and inflammation. The inflammatory component of diabetes remains under-characterized. Recent years have brought new insights into the possible mechanism involved in the increased inflammatory response, suggesting that environmental factors such as a westernized diet may participate in this process. Dietary lipids, particularly palmitate, are substrates for the biosynthesis of bioactive sphingolipids. Disturbed serum sphingolipid profiles were observed in both T1DM and T2DM patients. Many polymorphisms were identified in genes encoding enzymes of the sphingolipid pathway, including sphingosine kinase 2 (SK2), the S1P generating enzyme which is highly expressed in beta-cells. Proinflammatory cytokines and free fatty acids have been shown to modulate the expression and activity of S1P-generating and S1P-catabolizing enzymes. In this review, the similarities and differences in the action of extracellular and intracellular S1P in beta-cells exposed to cytokines or free fatty acids will be identified and the outlook for future research will be discussed. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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22 pages, 2333 KiB

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The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia

by Jaya M. Thomas, Tara Sudhadevi, Prathima Basa, Alison W. Ha, Viswanathan Natarajan and Anantha Harijith

Int. J. Mol. Sci. 2022, 23(3), 1254; https://doi.org/10.3390/ijms23031254 - 23 Jan 2022

Cited by 15 | Viewed by 3777

Abstract

Premature infants are born with developing lungs burdened by surfactant deficiency and a dearth of antioxidant defense systems. Survival rate of such infants has significantly improved due to advances in care involving mechanical ventilation and oxygen supplementation. However, a significant subset of such [...] Read more.

Premature infants are born with developing lungs burdened by surfactant deficiency and a dearth of antioxidant defense systems. Survival rate of such infants has significantly improved due to advances in care involving mechanical ventilation and oxygen supplementation. However, a significant subset of such survivors develops the chronic lung disease, Bronchopulmonary dysplasia (BPD), characterized by enlarged, simplified alveoli and deformed airways. Among a host of factors contributing to the pathogenesis is oxidative damage induced by exposure of the developing lungs to hyperoxia. Recent data indicate that hyperoxia induces aberrant sphingolipid signaling, leading to mitochondrial dysfunction and abnormal reactive oxygen species (ROS) formation (ROS). The role of sphingolipids such as ceramides and sphingosine 1-phosphate (S1P), in the development of BPD emerged in the last decade. Both ceramide and S1P are elevated in tracheal aspirates of premature infants of <32 weeks gestational age developing BPD. This was faithfully reflected in the murine models of hyperoxia and BPD, where there is an increased expression of sphingolipid metabolites both in lung tissue and bronchoalveolar lavage. Treatment of neonatal pups with a sphingosine kinase1 specific inhibitor, PF543, resulted in protection against BPD as neonates, accompanied by improved lung function and reduced airway remodeling as adults. This was accompanied by reduced mitochondrial ROS formation. S1P receptor1 induced by hyperoxia also aggravates BPD, revealing another potential druggable target in this pathway for BPD. In this review we aim to provide a detailed description on the role played by sphingolipid signaling in hyperoxia induced lung injury and BPD. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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13 pages, 2115 KiB

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Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

by José Villanueva, Yolanda Gimenez-Molina, Bazbek Davletov and Luis M. Gutiérrez

Int. J. Mol. Sci. 2022, 23(3), 1086; https://doi.org/10.3390/ijms23031086 - 19 Jan 2022

Cited by 2 | Viewed by 2817

Abstract

The fusion of membranes is a central part of the physiological processes involving the intracellular transport and maturation of vesicles and the final release of their contents, such as neurotransmitters and hormones, by exocytosis. Traditionally, in this process, proteins, such SNAREs have been [...] Read more.

The fusion of membranes is a central part of the physiological processes involving the intracellular transport and maturation of vesicles and the final release of their contents, such as neurotransmitters and hormones, by exocytosis. Traditionally, in this process, proteins, such SNAREs have been considered the essential components of the fusion molecular machinery, while lipids have been seen as merely structural elements. Nevertheless, sphingosine, an intracellular signalling lipid, greatly increases the release of neurotransmitters in neuronal and neuroendocrine cells, affecting the exocytotic fusion mode through the direct interaction with SNAREs. Moreover, recent studies suggest that FTY-720 (Fingolimod), a sphingosine structural analogue used in the treatment of multiple sclerosis, simulates sphingosine in the promotion of exocytosis. Furthermore, this drug also induces the intracellular fusion of organelles such as dense vesicles and mitochondria causing cell death in neuroendocrine cells. Therefore, the effect of sphingosine and synthetic derivatives on the heterologous and homologous fusion of organelles can be considered as a new mechanism of action of sphingolipids influencing important physiological processes, which could underlie therapeutic uses of sphingosine derived lipids in the treatment of neurodegenerative disorders and cancers of neuronal origin such neuroblastoma. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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46 pages, 3991 KiB

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Gangliosides as Biomarkers of Human Brain Diseases: Trends in Discovery and Characterization by High-Performance Mass Spectrometry

by Mirela Sarbu, Raluca Ica and Alina D. Zamfir

Int. J. Mol. Sci. 2022, 23(2), 693; https://doi.org/10.3390/ijms23020693 - 8 Jan 2022

Cited by 11 | Viewed by 3531

Abstract

Gangliosides are effective biochemical markers of brain pathologies, being also in the focus of research as potential therapeutic targets. Accurate brain ganglioside mapping is an essential requirement for correlating the specificity of their composition with a certain pathological state and establishing a well-defined [...] Read more.

Gangliosides are effective biochemical markers of brain pathologies, being also in the focus of research as potential therapeutic targets. Accurate brain ganglioside mapping is an essential requirement for correlating the specificity of their composition with a certain pathological state and establishing a well-defined set of biomarkers. Among all bioanalytical methods conceived for this purpose, mass spectrometry (MS) has developed into one of the most valuable, due to the wealth and consistency of structural information provided. In this context, the present article reviews the achievements of MS in discovery and structural analysis of gangliosides associated with severe brain pathologies. The first part is dedicated to the contributions of MS in the assessment of ganglioside composition and role in the specific neurodegenerative disorders: Alzheimer’s and Parkinson’s diseases. A large subsequent section is devoted to cephalic disorders (CD), with an emphasis on the MS of gangliosides in anencephaly, the most common and severe disease in the CD spectrum. The last part is focused on the major accomplishments of MS-based methods in the discovery of ganglioside species, which are associated with primary and secondary brain tumors and may either facilitate an early diagnosis or represent target molecules for immunotherapy oriented against brain cancers. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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23 pages, 1822 KiB

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Ceramide and Related Molecules in Viral Infections

by Nadine Beckmann and Katrin Anne Becker

Int. J. Mol. Sci. 2021, 22(11), 5676; https://doi.org/10.3390/ijms22115676 - 26 May 2021

Cited by 28 | Viewed by 5577

Abstract

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules [...] Read more.

Ceramide is a lipid messenger at the heart of sphingolipid metabolism. In concert with its metabolizing enzymes, particularly sphingomyelinases, it has key roles in regulating the physical properties of biological membranes, including the formation of membrane microdomains. Thus, ceramide and its related molecules have been attributed significant roles in nearly all steps of the viral life cycle: they may serve directly as receptors or co-receptors for viral entry, form microdomains that cluster entry receptors and/or enable them to adopt the required conformation or regulate their cell surface expression. Sphingolipids can regulate all forms of viral uptake, often through sphingomyelinase activation, and mediate endosomal escape and intracellular trafficking. Ceramide can be key for the formation of viral replication sites. Sphingomyelinases often mediate the release of new virions from infected cells. Moreover, sphingolipids can contribute to viral-induced apoptosis and morbidity in viral diseases, as well as virus immune evasion. Alpha-galactosylceramide, in particular, also plays a significant role in immune modulation in response to viral infections. This review will discuss the roles of ceramide and its related molecules in the different steps of the viral life cycle. We will also discuss how novel strategies could exploit these for therapeutic benefit. Full article

(This article belongs to the Special Issue Sphingolipids: Signals and Disease 2.0)

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