scholarly journals Aberrant DEGS1 sphingolipid metabolism impairs central and peripheral nervous system function in humans

2018 ◽  
Author(s):  
Gergely Karsai ◽  
Florian Kraft ◽  
Natja Haag ◽  
G Christoph Korenke ◽  
Benjamin Hänisch ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Neurological Disorder ◽  
Cell Model ◽  
Sphingolipid Metabolism ◽  
Significant Shift ◽  
Serine Palmitoyltransferase ◽  
Ceramide Synthesis ◽  
Sphingosine 1 Phosphate ◽  
Sheath Formation

Sphingolipids including ceramides are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids are associated with various neurological pathologies, however, the entire spectrum of disorders affecting sphingolipid metabolism remains elusive. By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous system, we identified a homozygous variant p.(Ala280Val) inDEGS1,encoding an enzyme of the ceramide synthesis pathway. The blood sphingolipid profile and patient-derived fibroblasts both showed a significant shift from the unsaturated to the dihydro-forms of sphingolipids. Moreover, an atypical and potentially toxic sphingolipid metabolite is formed as consequence of the altered synthesis pathway. The changes in the sphingolipid profile were recapitulated in a CRISPR/Cas-basedDEGS1knockout HAP1-cell model and by chemical inhibition of DEGS1, suggesting a loss of DEGS1 function in the disease. DEGS1 insufficiency is thus a novel cause for a multisystem neurological disorder. A sphingolipid-rich diet may correct the metabolic profile and improve the clinical outcome of affected individuals and suggests that this heritable condition might be treatable.AbbreviationsSLSphingolipidsSPTserine-palmitoyltransferaseCerCeramidesdhCerdihydroceramideS1Psphingosine-1-phosphateSOsphingosineHSANhereditary sensory and autonomic neuropathy

scholarly journals Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration

2021 ◽  
Vol 22 (14) ◽  
pp. 7353
Author(s):  
Maria Ayub ◽  
Hee-Kyung Jin ◽  
Jae-sung Bae
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodegenerative Disorders ◽  
Sphingolipid Metabolism ◽  
Bioactive Lipids ◽  
Metabolic Intermediates ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
The Central Nervous System ◽  
System Physiology

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.

scholarly journals Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis

2002 ◽  
Vol 158 (6) ◽  
pp. 1039-1049 ◽  
Author(s):  
Hervé Le Stunff ◽  
Ismael Galve-Roperh ◽  
Courtney Peterson ◽  
Sheldon Milstien ◽  
Sarah Spiegel
Keyword(s):  
Cell Fate ◽  
De Novo ◽  
Fumonisin B1 ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Serine Palmitoyltransferase ◽  
Intracellular Membranes ◽  
Sphingosine 1 Phosphate ◽  
Ceramide Accumulation ◽  
Membrane Treatment

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological processes by binding to a family of G protein–coupled receptors or as an intracellular second messenger. Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast. Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin. Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane. Treatment of SPP-1 transfectants with S1P markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis. Remarkably, dihydro-S1P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis. Ceramide accumulation induced by S1P was completely blocked by fumonisin B1, an inhibitor of ceramide synthase, but only partially reduced by myriocin, an inhibitor of serine palmitoyltransferase, the first committed step in de novo synthesis of ceramide. Furthermore, S1P, but not dihydro-S1P, stimulated incorporation of [3H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide. Collectively, our results suggest that SPP-1 functions in an unprecedented manner to regulate sphingolipid biosynthesis and is poised to influence cell fate.

scholarly journals Antioxidants Supplementation Reduces Ceramide Synthesis Improving the Cardiac Insulin Transduction Pathway in a Rodent Model of Obesity

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3413
Author(s):  
Katarzyna Hodun ◽  
Klaudia Sztolsztener ◽  
Adrian Chabowski
Keyword(s):  
Lipid Metabolism ◽  
Insulin Signaling ◽  
High Performance ◽  
Sphingolipid Metabolism ◽  
Intragastric Administration ◽  
Transduction Pathway ◽  
Ceramide Synthesis ◽  
Sphingosine 1 Phosphate ◽  
Male Wistar Rats ◽  
Ceramide Accumulation

Obesity-related disruption in lipid metabolism contributes to cardiovascular dysfunction. Despite numerous studies on lipid metabolism in the left ventricle, there is no data describing the influence of n-acetylcysteine (NAC) and α-lipoic acid (ALA), as glutathione precursors, on sphingolipid metabolism, and insulin resistance (IR) occurrence. The aim of our experiment was to evaluate the influence of chronic antioxidants administration on myocardial sphingolipid state and intracellular insulin signaling as a potential therapeutic strategy for obesity-related cardiovascular IR. The experiment was conducted on male Wistar rats fed a standard rodent chow or a high-fat diet with intragastric administration of NAC or ALA for eight weeks. Cardiac and plasma sphingolipid species were assessed by high-performance liquid chromatography (HPLC). The proteins expressed from sphingolipid and insulin signaling pathways were determined by Western blot. Antioxidant supplementation markedly reduced ceramide accumulation by lowering the expression of selected proteins from the sphingolipid pathway and simultaneously increased the myocardial sphingosine-1-phosphate level. Moreover, NAC and ALA augmented the expression of GLUT4 and the phosphorylation state of Akt (Ser473) and GSK3β (Ser9), which improved the intracellular insulin transduction pathway. Based on our results, we may postulate that NAC and ALA have a beneficial influence on the cardiac ceramidose under IR conditions.

scholarly journals A Dansyl-Modified Sphingosine Kinase Inhibitor Dpf-543 Enhanced de Novo Ceramide Generation

2021 ◽  
Author(s):  
Maftuna Shamshiddinova ◽  
Shokhid Gulyamov ◽  
Hee Jung Kim ◽  
Seo Hyeon Jung ◽  
Dong Jae Baek ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Sphingosine Kinase ◽  
Acid Sphingomyelinase ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Serine Palmitoyltransferase ◽  
Comparative Efficiency ◽  
Sphingosine 1 Phosphate

Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P was linked to the pathological outcome with inflammation, cancer metastasis or angiogenesis etc. In this regard, the SPHK/S1P axis regulation has been a specific issue in anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhance the serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs which eventually induced an unusual environment of the high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase) that contributes a partial increase on Cers. Collectively, a dansyl-modified DPF-543 relatively en-hanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.

scholarly journals A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation

2021 ◽  
Vol 22 (17) ◽  
pp. 9190
Author(s):  
Maftuna Shamshiddinova ◽  
Shokhid Gulyamov ◽  
Hee-Jung Kim ◽  
Seo-Hyeon Jung ◽  
Dong-Jae Baek ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Sphingosine Kinase ◽  
Acid Sphingomyelinase ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Serine Palmitoyltransferase ◽  
Comparative Efficiency ◽  
Sphingosine 1 Phosphate

Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P is linked to a pathological outcome with inflammation, cancer metastasis, or angiogenesis, etc. In this regard, SPHK/S1P axis regulation has been a specific issue in the anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhancing serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs, which eventually induced an unusual environment with a high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase), which contributes a partial increase in Cers. Collectively, a dansyl-modified DPF-543 relatively enhanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.

Glucuronyl 3-sulfate occurs exclusively on distal unmyelinated terminals of selected sensory neurons in the peripheral nervous system

1995 ◽  
Vol 53 ◽  
pp. 958-959
Author(s):  
S.S. Spicer ◽  
B.A. Schulte
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Peripheral Nervous System ◽  
Sensory Neurons ◽  
Sensory Nerves ◽  
Tissue Antigens ◽  
The Central Nervous System ◽  
The Brain ◽  
Leu 7

Generation of monoclonal antibodies (MAbs) against tissue antigens has yielded several (VC1.1, HNK- 1, L2, 4F4 and anti-leu 7) which recognize the unique sugar epitope, glucuronyl 3-sulfate (Glc A3- SO4). In the central nervous system, these MAbs have demonstrated Glc A3-SO4 at the surface of neurons in the cerebral cortex, the cerebellum, the retina and other widespread regions of the brain.Here we describe the distribution of Glc A3-SO4 in the peripheral nervous system as determined by immunostaining with a MAb (VC 1.1) developed against antigen in the cat visual cortex. Outside the central nervous system, immunoreactivity was observed only in peripheral terminals of selected sensory nerves conducting transduction signals for touch, hearing, balance and taste. On the glassy membrane of the sinus hair in murine nasal skin, just deep to the ringwurt, VC 1.1 delineated an intensely stained, plaque-like area (Fig. 1). This previously unrecognized structure of the nasal vibrissae presumably serves as a tactile end organ and to our knowledge is not demonstrable by means other than its selective immunopositivity with VC1.1 and its appearance as a densely fibrillar area in H&E stained sections.

Questions and Answers

2000 ◽  
Vol 5 (2) ◽  
pp. 3-3
Author(s):  
Christopher R. Brigham ◽  
James B. Talmage
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Spinal Nerve ◽  
Sensory Loss ◽  
Residual Symptoms ◽  
Additional Information ◽  
Questions And Answers ◽  
Motor Nerves ◽  
Symptoms And Signs ◽  
Limited Motion

Abstract Lesions of the peripheral nervous system (PNS), whether due to injury or illness, commonly result in residual symptoms and signs and, hence, permanent impairment. The AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) describes procedures for rating upper extremity neural deficits in Chapter 3, The Musculoskeletal System, section 3.1k; Chapter 4, The Nervous System, section 4.4 provides additional information and an example. The AMA Guides also divides PNS deficits into sensory and motor and includes pain within the former. The impairment estimates take into account typical manifestations such as limited motion, atrophy, and reflex, trophic, and vasomotor deficits. Lesions of the peripheral nervous system may result in diminished sensation (anesthesia or hypesthesia), abnormal sensation (dysesthesia or paresthesia), or increased sensation (hyperesthesia). Lesions of motor nerves can result in weakness or paralysis of the muscles innervated. Spinal nerve deficits are identified by sensory loss or pain in the dermatome or weakness in the myotome supplied. The steps in estimating brachial plexus impairment are similar to those for spinal and peripheral nerves. Evaluators should take care not to rate the same impairment twice, eg, rating weakness resulting from a peripheral nerve injury and the joss of joint motion due to that weakness.

Chronic neonatal mild stress induces long lasting alterations on peripheral nervous system programming in mice

2004 ◽  
Author(s):  
G. Galietta ◽  
A. Capasso ◽  
A. Fortuna ◽  
F. Fabi ◽  
P. Del Basso ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Mild Stress ◽  
System Programming
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