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Acid Sphingomyelinase

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Erich Gulbins – One of the best experts on this subject based on the ideXlab platform.

  • The Role of Acid Sphingomyelinase Inhibition in Repetitive Mild Traumatic Brain Injury.
    The Journal of surgical research, 2020
    Co-Authors: Grace M. Niziolek, Erich Gulbins, Michael J. Edwards, Richard S. Hoehn, Peter L. Jernigan, Aaron P. Seitz, Amy T. Makley, Michael D. Goodman

    Abstract:

    Abstract Background Chronic traumatic encephalopathy is a consequence of repetitive mild traumatic brain injury (rmTBI). These injuries can result in psychiatric disorders that are treated with amitriptyline. Amitriptyline improves neuronal regeneration in major depression via inhibition of Acid Sphingomyelinase. We hypothesized that Acid Sphingomyelinase inhibition would preserve neuronal regeneration and decrease depressive symptoms following rmTBI in a murine model. Methods A murine model of rmTBI was established using a weight-drop method. Mice were subjected to mTBI every other day for 7 d. Mice received amitriptyline injection 2 h prior to each mTBI. After the final mTBI, mice underwent behavioral studies or biochemical analysis. Hippocampi were analyzed for markers of neurogenesis and phosphorylated tau aggregation. Results Mice that underwent rmTBI showed increased hippocampal phosphorylated tau aggregation 1 mo following rmTBI as well as decreased neuronal regeneration by bromodeoxyuridine uptake and doublecortin immunohistochemistry. Mice with either genetic deficiency or pharmacologic inhibition of Acid Sphingomyelinase demonstrated improved neuronal regeneration and decreased phosphorylated tau aggregation compared to untreated rmTBI mice. Behavioral testing showed rmTBI mice spent significantly more time in the dark and waiting to initiate feeding compared to sham mice. These behaviors were partially prevented by the inhibition of Acid Sphingomyelinase. Conclusions We established a murine model of rmTBI that leads to tauopathy, depression, and impaired hippocampal neurogenesis. Inhibition of Acid Sphingomyelinase prevented the harmful neurologic and behavioral effects of rmTBI. These findings highlight an important opportunity to improve recovery or prevent neuropsychiatric decline in patients at risk for chronic traumatic encephalopathy.

  • Acid Sphingomyelinase Deficiency Ameliorates Farber Disease.
    International Journal of Molecular Sciences, 2019
    Co-Authors: Nadine Beckmann, Katrin Anne Becker, Stephanie Kadow, Fabian Schumacher, Melanie Kramer, Claudine Kühn, Walter J. Schulz-schaeffer, Michael J. Edwards, Burkhard Kleuser, Erich Gulbins

    Abstract:

    Farber disease is a rare lysosomal storage disorder resulting from Acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel Acid ceramidase deficiency model that mirrors the human disease closely. Acid Sphingomyelinase is the enzyme that generates ceramide upstream of Acid ceramidase in the lysosomes. Using our Acid ceramidase deficiency model, we tested if Acid Sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional Acid Sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred Acid ceramidase deficient mice with Acid Sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted Acid Sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of Acid ceramidase deficient mice with the Acid Sphingomyelinase inhibitor amitriptyline was toxic to Acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that Acid Sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional Acid Sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.

  • Pharmacological Inhibition of Acid Sphingomyelinase Ameliorates Experimental Autoimmune Encephalomyelitis.
    Neuro-Signals, 2019
    Co-Authors: Silke Walter, Erich Gulbins, Katrin Anne Becker, Ramona Halmer, Neda Haghayegh Jahromi, Andrea Schottek, Claudia Blatti, Laura Davies, Laura Schnoeder, Thomas Bertsch

    Abstract:

    BACKGROUND/AIMS Multiple sclerosis (MS) is one of the most common autoimmune disorders of the central nervous system (CNS) and the leading cause of neurological disability among young adults in the Western world. We have previously shown that the Acid Sphingomyelinase plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. METHODS We induced adoptively transferred EAE in wildtype and Acid Sphingomyelinase-deficient mice. In addition, we immunized mice with MOGaa35-55 to induce active EAE and treated the mice with amitriptyline, a functional inhibitor of the Acid Sphingomyelinase. We investigated symptoms of EAE, blood-brain barrier integrity and neuroinflammation. RESULTS In the model of adoptively transferred EAE we demonstrate that expression of Acid Sphingomyelinase in the recipients rather than on transferred encephalitogenic T cells contributes to the clinical development of EAE symptoms. To test if pharmacological targeting of Acid Sphingomyelinase can be explored for the development of novel therapies for MS, we inhibited Acid Sphingomyelinase with amitriptyline in mice in which EAE was induced by active immunization. We demonstrate that pharmacological inhibition of Acid Sphingomyelinase using amitriptyline protects against the development of EAE and markedly attenuates the characteristic detrimental neuroinflammatory response. CONCLUSION The studies identify the Acid Sphingomyelinase as a novel therapeutic target for treating MS patients.

Konrad Sandhoff – One of the best experts on this subject based on the ideXlab platform.

  • functional characterization of the postulated intramolecular sphingolipid activator protein domain of human Acid Sphingomyelinase
    Biological Chemistry, 2004
    Co-Authors: Melanie Kolzer, O. Bartelsen, K. Ferlinz, Silvia Locatelli Hoops, Florian Lang, Konrad Sandhoff

    Abstract:

    : Degradation of membrane-bound sphingomyelin to phosphorylcholine and ceramide is catalyzed by the water-soluble lysosomal Acid Sphingomyelinase (A-SMase). The presence of sphingolipid activator proteins (Saps: saposins A-D; GM2 activator) is not essential to mediate this reaction at the water-lipid interface in vivo . A hypothesis based on amino Acid sequence alignments suggests that the enzyme possesses an N-terminal saposin-homologous domain, which may facilitate the enzymatic reaction at the interface. We mutated one homologous and three conserved amino Acid residues of this domain and studied the activity of the variant enzymes using different sphingomyelin degradation assays. A variant with an exchange of a conserved amino Acid residue, Pro153Ala, still exhibited enzyme activity of approximately 52% of normal in a detergent-containing micellar assay, but only 13% of normal in a detergent-free liposomal assay system, which suggests that the Sap-homologous domain fulfills membrane-disturbing functions. Addition of saposin C to the liposomal assay mixtures increased the Pro153Ala variant Sphingomyelinase activity to 46% of normal, indicating that the variant saposin-like domain can be substituted by the presence of the sphingolipid activator protein. On the other hand, the addition of saposin C did not result in complete restoration of the variant activity. Thus, the Sap-like domain may also have another role, e.g., to stabilize the fold of Acid Sphingomyelinase, which cannot be compensated by the presence of saposin C or a detergent. Such an essential second function of the saposin-like domain as an integral part of Acid Sphingomyelinase is confirmed by our observation that the Lys118Glu, Cys120Ser and Cys131Ser variants were almost completely devoid of activity in the detergent-containing micellar assay system as well as in the liposomal assay system in the presence of saposin C.

  • Purification and Characterization of Recombinant, Human Acid Ceramidase CATALYTIC REACTIONS AND INTERACTIONS WITH Acid Sphingomyelinase
    The Journal of biological chemistry, 2003
    Co-Authors: Nozomu Okino, Konrad Sandhoff, Rajwinder Dhami, Arie Dagan, Shimon Gatt, Heike Schulze, Edward H. Schuchman

    Abstract:

    Abstract Human Acid ceramidase was overexpressed in Chinese hamster ovary cells by amplification of the transfected, full-length cDNA. The majority of the overexpressed enzyme was secreted into the culture media and purified to apparent homogeneity. The purified protein contained the same 13-(α) and 40 (β)–kDa subunits as human Acid ceramidase from natural sources, had an Acidic pH optimum (4.5), and followed normal Michaelis-Menten kinetics using 14C- and BODIPY-labeled C12-ceramide as substrates. Deglycosylation studies showed that the recombinant enzyme contained mostly “high mannose” type oligosaccharides and that two distinct β-subunits were present. Amino Acid sequencing of these subunit polypeptides revealed a single N terminus, suggesting that the ∼2–4-kDa molecular mass difference was likely due to C-terminal processing. The purified enzyme also catalyzed ceramide synthesis in vitro using 14C-labeled C12 fatty Acid and sphingosine as substrates. Surprisingly, we found that media from the overexpressing hamster cells had increased Acid Sphingomyelinase activity and that this activity could be co-precipitated with Acid ceramidase using anti-ceramidase antibodies. Overexpression of Acid ceramidase in normal human skin fibroblasts also led to enhanced Acid Sphingomyelinase secretion, but this was not observed in Niemann-Pick disease cells. RNA studies showed that this increased activity was not due to overexpression of the endogenous Acid Sphingomyelinase gene. Uptake studies using mouse macrophages revealed rapid internalization of the Acid ceramidase activity from the hamster cell media but not Acid Sphingomyelinase. These studies provide new insights into Acid ceramidase and the related lipid hydrolase, Acid Sphingomyelinase.

  • Phosphatidylinositol-3,5-Bisphosphate is a potent and selective inhibitor of Acid Sphingomyelinase.
    Biological chemistry, 2003
    Co-Authors: Melanie Kolzer, Heike Schulze, Christoph Arenz, Klaus Ferlinz, Norbert Werth, Ralf Klingenstein, Konrad Sandhoff

    Abstract:

    Acid Sphingomyelinase (A-SMase, EC 3.1.4.12) catalyzes the lysosomal degradation of sphingomyelin to phosphorylcholine and ceramide. Inherited deficiencies of Acid Sphingomyelinase activity result in various clinical forms of Niemann-Pick disease, which are characterised by massive lysosomal accumulation of sphingomyelin. Sphingomyelin hydrolysis by both, Acid Sphingomyelinase and membrane-associated neutral Sphingomyelinase, plays also an important role in cellular signaling systems regulating proliferation, apoptosis and differentiation. Here, we present a potent and selective novel inhibitor of A-SMase, L-alpha-phosphatidyl-D-myo-inositol-3,5-bisphosphate (PtdIns3,5P2), a naturally occurring substance detected in mammalian, plant and yeast cells. The inhibition constant Ki for the new A-SMase inhibitor PtdIns3,5P2 is 0.53 microM as determined in a micellar assay system with radiolabeled sphingomyelin as substrate and recombinant human A-SMase purified from insect cells. Even at concentrations of up to 50 microM, PtdIns3,5P2 neither decreased plasma membrane-associated, magnesium-dependent neutral Sphingomyelinase activity, nor was it an inhibitor of the lysosomal hydrolases beta-hexosaminidase A and Acid ceramidase. Other phosphoinositides tested had no or a much weaker effect on Acid Sphingomyelinase. Different inositol-bisphosphates were studied to elucidate structure-activity relationships for A-SMase inhibition. Our investigations provide an insight into the structural features required for selective, efficient inhibition of Acid Sphingomyelinase and may also be used as starting point for the development of new potent A-SMase inhibitors optimised for diverse applications.

Katrin Anne Becker – One of the best experts on this subject based on the ideXlab platform.

  • Acid Sphingomyelinase Deficiency Ameliorates Farber Disease.
    International Journal of Molecular Sciences, 2019
    Co-Authors: Nadine Beckmann, Katrin Anne Becker, Stephanie Kadow, Fabian Schumacher, Melanie Kramer, Claudine Kühn, Walter J. Schulz-schaeffer, Michael J. Edwards, Burkhard Kleuser, Erich Gulbins

    Abstract:

    Farber disease is a rare lysosomal storage disorder resulting from Acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel Acid ceramidase deficiency model that mirrors the human disease closely. Acid Sphingomyelinase is the enzyme that generates ceramide upstream of Acid ceramidase in the lysosomes. Using our Acid ceramidase deficiency model, we tested if Acid Sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional Acid Sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred Acid ceramidase deficient mice with Acid Sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted Acid Sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of Acid ceramidase deficient mice with the Acid Sphingomyelinase inhibitor amitriptyline was toxic to Acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that Acid Sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional Acid Sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.

  • Pharmacological Inhibition of Acid Sphingomyelinase Ameliorates Experimental Autoimmune Encephalomyelitis.
    Neuro-Signals, 2019
    Co-Authors: Silke Walter, Erich Gulbins, Katrin Anne Becker, Ramona Halmer, Neda Haghayegh Jahromi, Andrea Schottek, Claudia Blatti, Laura Davies, Laura Schnoeder, Thomas Bertsch

    Abstract:

    BACKGROUND/AIMS Multiple sclerosis (MS) is one of the most common autoimmune disorders of the central nervous system (CNS) and the leading cause of neurological disability among young adults in the Western world. We have previously shown that the Acid Sphingomyelinase plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. METHODS We induced adoptively transferred EAE in wildtype and Acid Sphingomyelinase-deficient mice. In addition, we immunized mice with MOGaa35-55 to induce active EAE and treated the mice with amitriptyline, a functional inhibitor of the Acid Sphingomyelinase. We investigated symptoms of EAE, blood-brain barrier integrity and neuroinflammation. RESULTS In the model of adoptively transferred EAE we demonstrate that expression of Acid Sphingomyelinase in the recipients rather than on transferred encephalitogenic T cells contributes to the clinical development of EAE symptoms. To test if pharmacological targeting of Acid Sphingomyelinase can be explored for the development of novel therapies for MS, we inhibited Acid Sphingomyelinase with amitriptyline in mice in which EAE was induced by active immunization. We demonstrate that pharmacological inhibition of Acid Sphingomyelinase using amitriptyline protects against the development of EAE and markedly attenuates the characteristic detrimental neuroinflammatory response. CONCLUSION The studies identify the Acid Sphingomyelinase as a novel therapeutic target for treating MS patients.

  • Blockade of Experimental Multiple Sclerosis by Inhibition of the Acid Sphingomyelinase/Ceramide System.
    Neuro-Signals, 2017
    Co-Authors: Katrin Anne Becker, Erich Gulbins, Brian Henry, Ramona Halmer, Laura Davies, Klaus Fassbender, Regan Ziobro-henry, Yann Decker, Yang Liu, Silke Walter

    Abstract:

    BACKGROUND Multiple sclerosis (MS) is a severe and common autoimmune disorder of the central nervous system. Despite the availability of several novel treatment options, the disease is still poorly controlled, since the pathophysiological mechanisms are not fully understood. METHODS We tested the role of the Acid Sphingomyelinase/ceramide system in a model of MS, i.e. experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin-oligodendrocyte glycoprotein and the development of the disease was analyzed by histology, immunological tests and clinical assessment in wildtype and Acid Sphingomyelinase (Asm)-deficient mice. RESULTS Genetic deficiency of Acid Sphingomyelinase (Asm) protected against clinical symptoms in EAE and markedly attenuated the characteristic detrimental neuroinflammatory response. T lymphocyte adhesion, integrity of tight junctions, blood-brain barrier disruption and subsequent intracerebral infiltration of inflammatory cells were blocked in Asm-deficient mice after immunization. This resulted in an almost complete block of the development of disease symptoms in these mice, while wildtype mice showed severe neurological symptoms typical for EAE. CONCLUSION Activation of the Asm/ceramide system is a central step for the development of EAE. Our findings may serve to identify novel therapeutic strategies for MS patients.