The Experts below are selected from a list of 4737 Experts worldwide ranked by ideXlab platform
Alexandre Henriques - One of the best experts on this subject based on the ideXlab platform.
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ambroxol hydrochloride improves motor functions and extends survival in a mouse model of familial amyotrophic lateral sclerosis
Frontiers in Pharmacology, 2019Co-Authors: Alexandra Bouscary, Jean-philippe Loeffler, Michael Spedding, Cyril Quessada, Althea Mosbach, Noelle Callizot, Alexandre HenriquesAbstract:Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS. In particular, levels of ceramides, Glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients. Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase. Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice. A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice. In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit. Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.
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Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis
Scientific Reports, 2017Co-Authors: Alexandre Henriques, Mylene Huebecker, David A. Priestman, Helene Blasco, Céline Keime, Philippe Corcia, Christian R. Andres, Frances M. Platt, Michael Spedding, Jean-philippe LoefflerAbstract:Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and Glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers Glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1^G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of Glucosylceramide may be a therapeutic target for this devastating disease.
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amyotrophic lateral sclerosis and denervation alter sphingolipids and up regulate Glucosylceramide synthase
Human Molecular Genetics, 2015Co-Authors: Alexandre Henriques, David A. Priestman, Vincent Croixmarie, Angela Rosenbohm, Sylvie Dirriggrosch, Eleonora Dambra, Mylene HuebeckerAbstract:Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. Growing evidence suggests a link between changes in lipid metabolism and ALS. Here, we used UPLC/TOF-MS to survey the lipidome in SOD1(G86R) mice, a model of ALS. Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology. In silico analysis also revealed appreciable changes in sphingolipids including ceramides and Glucosylceramides (GlcCer). HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates. Glucosylceramide synthase (GCS), the enzyme responsible for GlcCer biosynthesis, was up-regulated in muscle of SOD1(G86R) mice and ALS patients, and in muscle of wild-type mice after surgically induced denervation. Conversely, inhibition of GCS in wild-type mice, following transient peripheral nerve injury, reversed the overexpression of genes in muscle involved in oxidative metabolism and delayed motor recovery. GCS inhibition in SOD1(G86R) mice also affected the expression of metabolic genes and induced a loss of muscle strength and morphological deterioration of the motor endplates. These findings suggest that GSLs may play a critical role in ALS muscle pathology and could lead to the identification of new therapeutic targets.
Jean-philippe Loeffler - One of the best experts on this subject based on the ideXlab platform.
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ambroxol hydrochloride improves motor functions and extends survival in a mouse model of familial amyotrophic lateral sclerosis
Frontiers in Pharmacology, 2019Co-Authors: Alexandra Bouscary, Jean-philippe Loeffler, Michael Spedding, Cyril Quessada, Althea Mosbach, Noelle Callizot, Alexandre HenriquesAbstract:Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS. In particular, levels of ceramides, Glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients. Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase. Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice. A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice. In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit. Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.
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Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis
Scientific Reports, 2017Co-Authors: Alexandre Henriques, Mylene Huebecker, David A. Priestman, Helene Blasco, Céline Keime, Philippe Corcia, Christian R. Andres, Frances M. Platt, Michael Spedding, Jean-philippe LoefflerAbstract:Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and Glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers Glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1^G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of Glucosylceramide may be a therapeutic target for this devastating disease.
Michael Spedding - One of the best experts on this subject based on the ideXlab platform.
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ambroxol hydrochloride improves motor functions and extends survival in a mouse model of familial amyotrophic lateral sclerosis
Frontiers in Pharmacology, 2019Co-Authors: Alexandra Bouscary, Jean-philippe Loeffler, Michael Spedding, Cyril Quessada, Althea Mosbach, Noelle Callizot, Alexandre HenriquesAbstract:Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS. In particular, levels of ceramides, Glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients. Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase. Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice. A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice. In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit. Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.
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Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis
Scientific Reports, 2017Co-Authors: Alexandre Henriques, Mylene Huebecker, David A. Priestman, Helene Blasco, Céline Keime, Philippe Corcia, Christian R. Andres, Frances M. Platt, Michael Spedding, Jean-philippe LoefflerAbstract:Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and Glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers Glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1^G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of Glucosylceramide may be a therapeutic target for this devastating disease.
Hiroshi Kitagaki - One of the best experts on this subject based on the ideXlab platform.
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Glycosylceramide modifies the flavor and metabolic characteristics of sake yeast
PeerJ Inc., 2018Co-Authors: Jannatul Ferdouse, Yuki Yamamoto, Seiga Taguchi, Yumiko Yoshizaki, Kazunori Takamine, Hiroshi KitagakiAbstract:In the manufacture of sake, Japanese traditional rice wine, sake yeast is fermented with koji, which is steamed rice fermented with the non-pathogenic fungus Aspergillus oryzae. During fermentation, sake yeast requires lipids, such as unsaturated fatty acids and sterols, in addition to substances provided by koji enzymes for fermentation. However, the role of sphingolipids on the brewing characteristics of sake yeast has not been studied. In this study, we revealed that glycosylceramide, one of the sphingolipids abundant in koji, affects yeast fermentation. The addition of soy, A. oryzae, and Grifola frondosa glycosylceramide conferred a similar effect on the flavor profiles of sake yeast. In particular, the addition of A. oryzae and G. frondosa glycosylceramide were very similar in terms of the decreases in ethyl caprylate and ethyl 9-decenoate. The addition of soy glycosylceramide induced metabolic changes to sake yeast such as a decrease in glucose, increases in ethanol and glycerol and changes in several amino acids and organic acids concentrations. Tricarboxylic acid (TCA) cycle, pyruvate metabolism, starch and sucrose metabolism, and glycerolipid metabolism were overrepresented in the cultures incubated with sake yeast and soy glycosylceramide. This is the first study of the effect of glycosylceramide on the flavor and metabolic profile of sake yeast
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japanese traditional dietary fungus koji aspergillus oryzae functions as a prebiotic for blautia coccoides through glycosylceramide japanese dietary fungus koji is a new prebiotic
SpringerPlus, 2016Co-Authors: Hiroshi Hamajima, Haruka Matsunaga, Ayami Fujikawa, Tomoya Sato, Susumu Mitsutake, Teruyoshi Yanagita, Koji Nagao, Jiro Nakayama, Hiroshi KitagakiAbstract:Background The Japanese traditional cuisine, Washoku, considered to be responsible for increased longevity among the Japanese, comprises various foods fermented with the non-pathogenic fungus Aspergillus oryzae (koji). We have recently revealed that koji contains an abundant amount of glycosylceramide. Intestinal microbes have significant effect on health. However, the effects of koji glycosylceramide on intestinal microbes have not been studied.
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japanese traditional dietary fungus koji aspergillus oryzae functions as a prebiotic for blautia coccoides through glycosylceramide japanese dietary fungus koji is a new prebiotic
SpringerPlus, 2016Co-Authors: Hiroshi Hamajima, Haruka Matsunaga, Ayami Fujikawa, Tomoya Sato, Susumu Mitsutake, Teruyoshi Yanagita, Koji Nagao, Jiro Nakayama, Hiroshi KitagakiAbstract:The Japanese traditional cuisine, Washoku, considered to be responsible for increased longevity among the Japanese, comprises various foods fermented with the non-pathogenic fungus Aspergillus oryzae (koji). We have recently revealed that koji contains an abundant amount of glycosylceramide. Intestinal microbes have significant effect on health. However, the effects of koji glycosylceramide on intestinal microbes have not been studied. Glycosylceramide was extracted and purified from koji. C57BL/6N mice were fed a diet containing 1 % purified koji glycosylceramide for 1 week. Nutritional parameters and faecal lipid constituents were analyzed. The intestinal microbial flora of mice on this diet was investigated. Ingested koji glycosylceramide was neither digested by intestinal enzymes nor was it detected in the faeces, suggesting that koji glycosylceramide was digested by the intestinal microbial flora. Intestinal microbial flora that digested koji glycosylceramide had an increased ratio of Blautia coccoides. Stimulation of B. coccoides growth by pure koji glycosylceramide was confirmed in vitro. Koji functions as a prebiotic for B. coccoides through glycosylceramide. Since there are many reports of the effects of B. coccoides on health, an increase in intestinal B. coccoides by koji glycosylceramide might be the connection between Japanese cuisine, intestinal microbial flora, and longevity.
Yildiz Yildiz - One of the best experts on this subject based on the ideXlab platform.
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accumulation of Glucosylceramide in the absence of the beta glucosidase gba2 alters cytoskeletal dynamics
PLOS Genetics, 2015Co-Authors: Diana N Raju, Sophie Schonauer, Hussein Hamzeh, Kevin C Flynn, Frank Bradke, Katharina Vom Dorp, Peter Dormann, Yildiz Yildiz, Christian Trotschel, Ansgar PoetschAbstract:Glycosphingolipids are key elements of cellular membranes, thereby, controlling a variety of cellular functions. Accumulation of the simple glycosphingolipid Glucosylceramide results in life-threatening lipid storage-diseases or in male infertility. How Glucosylceramide regulates cellular processes is ill defined. Here, we reveal that Glucosylceramide accumulation in GBA2 knockout-mice alters cytoskeletal dynamics due to a more ordered lipid organization in the plasma membrane. In dermal fibroblasts, accumulation of Glucosylceramide augments actin polymerization and promotes microtubules persistence, resulting in a higher number of filopodia and lamellipodia and longer microtubules. Similar cytoskeletal defects were observed in male germ and Sertoli cells from GBA2 knockout-mice. In particular, the organization of F-actin structures in the ectoplasmic specialization and microtubules in the sperm manchette is affected. Thus, Glucosylceramide regulates cytoskeletal dynamics, providing mechanistic insights into how Glucosylceramide controls signaling pathways not only during sperm development, but also in other cell types.
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beta glucosidase 1 gba1 is a second bile acid β glucosidase in addition to β glucosidase 2 gba2 study in β glucosidase deficient mice and humans
Biochemical and Biophysical Research Communications, 2012Co-Authors: Klaus Harzer, Yotam Blechhermoni, Ehud Goldin, Ursula Felderhoffmueser, Claudia Igney, Ellen Sidransky, Yildiz YildizAbstract:Abstract Beta-glucosidase 1 (GBA1; lysosomal glucocerebrosidase) and β-glucosidase 2 (GBA2, non-lysosomal glucocerebrosidase) both have Glucosylceramide as a main natural substrate. The enzyme-deficient conditions with Glucosylceramide accumulation are Gaucher disease (GBA−/− in humans), modelled by the Gba−/− mouse, and the syndrome with male infertility in the Gba2−/− mouse, respectively. Before the leading role of Glucosylceramide was recognised for both deficient conditions, bile acid-3-O-β-glucoside (BG), another natural substrate, was viewed as the main substrate of GBA2. Given that GBA2 hydrolyses both BG and Glucosylceramide, it was asked whether vice versa GBA1 hydrolyses both Glucosylceramide and BG. Here we show that GBA1 also hydrolyses BG. We compared the residual BG hydrolysing activities in the GBA1−/−, Gba1−/− conditions (where GBA2 is the almost only active β-glucosidase) and those in the Gba2−/− condition (GBA1 active), with wild-type activities, but we used also the GBA1 inhibitor isofagomine. GBA1 and GBA2 activities had characteristic differences between the studied fibroblast, liver and brain samples. Independently, the hydrolysis of BG by pure recombinant GBA1 was shown. The fact that both GBA1 and GBA2 are glucocerebrosidases as well as bile acid β-glucosidases raises the question, why lysosomal accumulation of Glucosylceramide in GBA1 deficiency, and extra-lysosomal accumulation in GBA2 deficiency, are not associated with an accumulation of BG in either condition.
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accumulation of Glucosylceramide in murine testis caused by inhibition of beta glucosidase 2 implications for spermatogenesis
Journal of Biological Chemistry, 2007Co-Authors: Charlotte M Walden, Frances M. Platt, Yildiz Yildiz, Roger Sandhoff, Chiachen Chuang, Terry D Butters, Raymond A Dwek, Aarnoud C Van Der SpoelAbstract:Abstract One of the hallmarks of male germ cell development is the formation of a specialized secretory organelle, the acrosome. This process can be pharmacologically disturbed in C57BL/6 mice, and thus infertility can be induced, by small molecular sugar-like compounds (alkylated imino sugars). Here the biochemical basis of this effect has been investigated. Our findings suggest that in vivo alkylated imino sugars primarily interact with the non-lysosomal glucosylceramidase. This enzyme cleaves Glucosylceramide into glucose and ceramide, is sensitive to imino sugars in vitro, and has been characterized as β-glucosidase 2 (GBA2). Imino sugars raised the level of Glucosylceramide in brain, spleen, and testis, in a dose-dependent fashion. In testis, multiple species of Glucosylceramide were similarly elevated, those having long acyl chains (C16–24), as well as those with very long polyunsaturated acyl chains (C28–30:5). Both of these GlcCer species were also increased in the testes from GBA2-deficient mice. When considering that the very long polyunsaturated sphingolipids are restricted to germ cells, these results indicate that in the testis GBA2 is present in both somatic and germ cells. Furthermore, in all mouse strains tested imino sugar treatment caused a rise in testicular Glucosylceramide, even in a number of strains, of which the males remain fertile after drug administration. Therefore, it appears that acrosome formation can be derailed by accumulation of Glucosylceramide in an extralysosomal localization, and that the sensitivity of male germ cells to Glucosylceramide is genetically determined.
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mutation of β glucosidase 2 causes glycolipid storage disease and impaired male fertility
Journal of Clinical Investigation, 2006Co-Authors: Yildiz Yildiz, H Matern, Bonne M Thompson, Jeremy C Allegood, Rebekkah L Warren, Denise M O Ramirez, Robert E Hammer, Kent F Hamra, S Matern, David W RussellAbstract:beta-Glucosidase 2 (GBA2) is a resident enzyme of the endoplasmic reticulum thought to play a role in the metabolism of bile acid-glucose conjugates. To gain insight into the biological function of this enzyme and its substrates, we generated mice deficient in GBA2 and found that these animals had normal bile acid metabolism. Knockout males exhibited impaired fertility. Microscopic examination of sperm revealed large round heads (globozoospermia), abnormal acrosomes, and defective mobility. Glycolipids, identified as Glucosylceramides by mass spectrometry, accumulated in the testes, brains, and livers of the knockout mice but did not cause obvious neurological symptoms, organomegaly, or a reduction in lifespan. Recombinant GBA2 hydrolyzed Glucosylceramide to glucose and ceramide; the same reaction catalyzed by the beta-glucosidase acid 1 (GBA1) defective in subjects with the Gaucher's form of lysosomal storage disease. We conclude that GBA2 is a glucosylceramidase whose loss causes accumulation of glycolipids and an endoplasmic reticulum storage disease.
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Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility
American Society for Clinical Investigation, 2006Co-Authors: Yildiz Yildiz, Matern Heidrun, Thompson Bonne, Allegood, Jeremy C., Warren, Rebekkah L., Ramirez, Denise M.o., Hammer, Robert E., Hamra F. Kent, Matern Siegfried, Russell, David W.Abstract:β-Glucosidase 2 (GBA2) is a resident enzyme of the endoplasmic reticulum thought to play a role in the metabolism of bile acid–glucose conjugates. To gain insight into the biological function of this enzyme and its substrates, we generated mice deficient in GBA2 and found that these animals had normal bile acid metabolism. Knockout males exhibited impaired fertility. Microscopic examination of sperm revealed large round heads (globozoospermia), abnormal acrosomes, and defective mobility. Glycolipids, identified as Glucosylceramides by mass spectrometry, accumulated in the testes, brains, and livers of the knockout mice but did not cause obvious neurological symptoms, organomegaly, or a reduction in lifespan. Recombinant GBA2 hydrolyzed Glucosylceramide to glucose and ceramide; the same reaction catalyzed by the β-glucosidase acid 1 (GBA1) defective in subjects with the Gaucher’s form of lysosomal storage disease. We conclude that GBA2 is a glucosylceramidase whose loss causes accumulation of glycolipids and an endoplasmic reticulum storage disease