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Article ; Online: Prevalence of Cancer in Acid Sphingomyelinase Deficiency

Wladimir Mauhin / Thierry Levade / Marie T. Vanier / Roseline Froissart / Olivier Lidove

Journal of Clinical Medicine, Vol 10, Iss 5029, p

2021 Volume 5029

Abstract: Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We ... ...

Abstract	Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We retrospectively reviewed the medical records of the adult chronic visceral ASMD patients in our cohort. Thirty-one patients (12 females, 19 males) were included with a median age of 48.7 y. (IQ: 30.3–55.1). Five cancers were observed in 1 female (breast cancer) and 4 males (two lung cancers, one thyroid cancer and one bladder cancer), resulting in a prevalence of 16.1%. The existence of cancer was associated with a more severe ASMD characterised by a larger spleen (25 cm (22.5–25) vs. 18 cm (17–20); p = 0.042); lower diffusing capacity of the lung for carbon monoxide (DLCO; 29.5 % (17.8–43.0) vs. 58.5 % (49.8–69.5%); p = 0.01) and tobacco use (100% vs. 45%; p = 0.04). Three patients died, all from cancer ( p = 0.002). The prevalence of cancer appeared to be strikingly elevated in our cohort of patients, without any specificity in the type of cancer. Systematic screening for cancer should be performed, and carcinogenic substances such as tobacco should be avoided in patients with ASMD.
Keywords	acid sphingomyelinase deficiency ; cancer ; ceramide ; lysosomal storage disease ; Niemann–Pick disease ; Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: GM2-GM3 gangliosides ratio is dependent on GRP94 through down-regulation of GM2-AP cofactor in brain metastasis cells

Carmen Bedia / Miriam Badia / Laia Muixí / Thierry Levade / Romà Tauler / Angels Sierra

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract GRP94 is an ATP-dependent chaperone able to regulate pro-oncogenic signaling pathways. Previous studies have shown a critical role of GRP94 in brain metastasis (BrM) pathogenesis and progression. In this work, an untargeted lipidomic analysis ... ...

Abstract	Abstract GRP94 is an ATP-dependent chaperone able to regulate pro-oncogenic signaling pathways. Previous studies have shown a critical role of GRP94 in brain metastasis (BrM) pathogenesis and progression. In this work, an untargeted lipidomic analysis revealed that some lipid species were altered in GRP94-deficient cells, specially GM2 and GM3 gangliosides. The catalytic pathway of GM2 is affected by the low enzymatic activity of β-Hexosaminidase (HexA), responsible for the hydrolysis of GM2 to GM3. Moreover, a deficiency of the GM2-activator protein (GM2-AP), the cofactor of HexA, is observed without alteration of gene expression, indicating a post-transcriptional alteration of GM2-AP in the GRP94-ablated cells. One plausible explanation of these observations is that GM2-AP is a client of GRP94, resulting in defective GM2 catabolic processing and lysosomal accumulation of GM2 in GRP94-ablated cells. Overall, given the role of gangliosides in cell surface dynamics and signaling, their imbalance might be linked to modifications of cell behaviour acquired in BrM progression. This work indicates that GM2-AP could be an important factor in ganglioside balance maintenance. These findings highlight the relevance of GM3 and GM2 gangliosides in BrM and reveal GM2-AP as a promising diagnosis and therapeutic target in BrM research.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: New Insights into the Role of Sphingolipid Metabolism in Melanoma

Lorry Carrié / Mathieu Virazels / Carine Dufau / Anne Montfort / Thierry Levade / Bruno Ségui / Nathalie Andrieu-Abadie

Cells, Vol 9, Iss 1967, p

2020 Volume 1967

Abstract: Cutaneous melanoma is a deadly skin cancer whose aggressiveness is directly linked to its metastatic potency. Despite remarkable breakthroughs in term of treatments with the emergence of targeted therapy and immunotherapy, the prognosis for metastatic ... ...

Abstract	Cutaneous melanoma is a deadly skin cancer whose aggressiveness is directly linked to its metastatic potency. Despite remarkable breakthroughs in term of treatments with the emergence of targeted therapy and immunotherapy, the prognosis for metastatic patients remains uncertain mainly because of resistances. Better understanding the mechanisms responsible for melanoma progression is therefore essential to uncover new therapeutic targets. Interestingly, the sphingolipid metabolism is dysregulated in melanoma and is associated with melanoma progression and resistance to treatment. This review summarises the impact of the sphingolipid metabolism on melanoma from the initiation to metastatic dissemination with emphasis on melanoma plasticity, immune responses and resistance to treatments.
Keywords	cancer ; ceramide ; gangliosides ; immunotherapy ; metastasis ; phenotype switching ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Acid ceramidase deficiency

Fabian P. S. Yu / Samuel Amintas / Thierry Levade / Jeffrey A. Medin

Orphanet Journal of Rare Diseases, Vol 13, Iss 1, Pp 1-

Farber disease and SMA-PME

2018 Volume 19

Abstract: Abstract Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). ...

Abstract	Abstract Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.
Keywords	Ceramide ; Lysosomal storage disorder ; SMA-PME ; Sphingolipid ; Lysosome ; Neuromuscular disease ; Medicine ; R
Subject code	610
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors

Cécile Baudoin-Dehoux / Tessa Castellan / Frédéric Rodriguez / Arnaud Rives / Fabien Stauffert / Virginie Garcia / Thierry Levade / Philippe Compain / Yves Génisson

Molecules, Vol 24, Iss 2, p

2019 Volume 354

Abstract: A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an ... ...

Abstract	A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal β-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.
Keywords	iminosugars ; glucocerebrosidase ; pharmacological chaperones ; glycosidase inhibitors ; glucosylceramide synthase inhibitors ; Gaucher disease ; ligand docking ; Organic chemistry ; QD241-441
Subject code	540
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: First Report of a Patient with MPS Type VII, Due to Novel Mutations in GUSB , Who Underwent Enzyme Replacement and Then Hematopoietic Stem Cell Transplantation

Patricia Dubot / Frédérique Sabourdy / Geneviève Plat / Charlotte Jubert / Claude Cancès / Pierre Broué / Guy Touati / Thierry Levade

International Journal of Molecular Sciences, Vol 20, Iss 21, p

2019 Volume 5345

Abstract: We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase ( GUSB) variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather ... ...

Abstract	We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase ( GUSB) variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather common c.526C>T, inherited from his father. Expression of these variations in transfected HEK293T cells demonstrated that the double mutation c.422A>C;424C>T reduces β-glucuronidase enzyme activity. Enzyme replacement therapy (ERT), using UX003 (vestronidase alfa), was started at four months of age, followed by a hematopoietic stem cell allograft transplantation (HSCT) at 13 months of age. ERT was well tolerated and attenuated visceromegaly and skin infiltration. After a severe skin and gut graft-versus-host disease, ERT was stopped six months after HSCT. The last follow-up examination (at the age of four years) revealed a normal psychomotor development, stabilized growth curve, no hepatosplenomegaly, and no other organ involvement. Intriguingly, enzyme activity had normalized in leukocytes but remained low in plasma. This case report illustrates: (i) The need for an early diagnosis of MPS, and (ii) the possible benefit of a very early enzymatic and/or cellular therapy in this rare form of lysosomal storage disease.
Keywords	mucopolysaccharidosis ; enzyme replacement therapy ; transplantation ; glycosaminoglycan ; glucuronidase ; sly syndrome ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sphingolipid paracrine signaling impairs keratinocyte adhesion to promote melanoma invasion

Cell Reports, Vol 42, Iss 12, Pp 113586- (2023)

2023

Abstract: Summary: Melanoma is the deadliest form of skin cancer due to its propensity to metastasize. It arises from melanocytes, which are attached to keratinocytes within the basal epidermis. Here, we hypothesize that, in addition to melanocyte-intrinsic ... ...

Abstract	Summary: Melanoma is the deadliest form of skin cancer due to its propensity to metastasize. It arises from melanocytes, which are attached to keratinocytes within the basal epidermis. Here, we hypothesize that, in addition to melanocyte-intrinsic modifications, dysregulation of keratinocyte functions could initiate early-stage melanoma cell invasion. We identified the lysolipid sphingosine 1-phosphate (S1P) as a tumor paracrine signal from melanoma cells that modifies the keratinocyte transcriptome and reduces their adhesive properties, leading to tumor invasion. Mechanistically, tumor cell-derived S1P reduced E-cadherin expression in keratinocytes via S1P receptor dependent Snail and Slug activation. All of these effects were blocked by S1P2/3 antagonists. Importantly, we showed that epidermal E-cadherin expression was inversely correlated with the expression of the S1P-producing enzyme in neighboring tumors and the Breslow thickness in patients with early-stage melanoma. These findings support the notion that E-cadherin loss in the epidermis initiates the metastatic cascade in melanoma.
Keywords	CP: Cancer ; CP: Metabolism ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparing ultrafiltration and equilibrium dialysis to measure unbound plasma dolutegravir concentrations based on a design of experiment approach

David Metsu / Thomas Lanot / François Fraissinet / Didier Concordet / Véronique Gayrard / Manon Averseng / Alice Ressault / Guillaume Martin-Blondel / Thierry Levade / Frédéric Février / Etienne Chatelut / Pierre Delobel / Peggy Gandia

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 8

Abstract: Abstract Dolutegravir therapeutic drug monitoring (TDM) could be improved by measuring the unbound dolutegravir plasma concentration (Cu), particularly in patients experiencing virological failure or toxicity despite achieving appropriate DTG total ... ...

Abstract	Abstract Dolutegravir therapeutic drug monitoring (TDM) could be improved by measuring the unbound dolutegravir plasma concentration (Cu), particularly in patients experiencing virological failure or toxicity despite achieving appropriate DTG total plasma concentrations. Equilibrium dialysis (ED) is the gold standard to measure Cu, but ED is time consuming, precluding its use in clinical practice. In contrast, ultrafiltration is applicable to TDM, but is sensitive to numerous analytical conditions. In order to evaluate measurements of Cu by ultrafiltration, ultrafiltration conditions were validated by comparison with ED. DTG concentrations were measured by LC–MS/MS. Three ultrafiltration factors (temperature, duration and relative centrifugal force [RCF]) were evaluated and compared to ED (25/37 °C), using a design of experiment strategy. Temperature was found to influence Cu results by ED (p = 0.036) and UF (p = 0.002) when results were analysed with ANOVA. Relative centrifugal force (2000 g) and time (20 min) interacted to influence Cu (p = 0.006), while individually they did not influence Cu (p = 0.88 and p = 0.42 for RCF and time). Ultrafiltration conditions which yielded the most comparable results to ED were 37 °C, 1000 g for 20 min. Ultrafiltration results greatly depended on analytical conditions, confirming the need to validate the method by comparison with ED in order to correctly interpret DTG Cu.
Keywords	Medicine ; R ; Science ; Q
Subject code	660
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Monogenic neurological disorders of sphingolipid metabolism

Sabourdy, Frédérique / Bruno Ségui / Céline Colacios / Leonardo Astudillo / Marguerite Mrad / Nathalie Andrieu-Abadie / Patricia Dubot / Thierry Levade

Biochimica et biophysica acta. 2015 Aug., v. 1851, no. 8

2015

Abstract: Sphingolipids comprise a wide variety of molecules containing a sphingoid long-chain base that can be N-acylated. These lipids are particularly abundant in the central nervous system, being membrane components of neurons as well as non-neuronal cells. ... ...

Abstract	Sphingolipids comprise a wide variety of molecules containing a sphingoid long-chain base that can be N-acylated. These lipids are particularly abundant in the central nervous system, being membrane components of neurons as well as non-neuronal cells. Direct evidence that these brain lipids play critical functions in brain physiology is illustrated by the dramatic consequences of genetic disturbances of their metabolism. Inherited defects of both synthesis and catabolism of sphingolipids are now identified in humans. These monogenic disorders are due to mutations in the genes encoding for the enzymes that catalyze either the formation or degradation of simple sphingolipids such as ceramides, or complex sphingolipids like glycolipids. They cause varying degrees of central nervous system dysfunction, quite similarly to the neurological disorders induced in mice by gene disruption of the corresponding enzymes. Herein, the enzyme deficiencies and metabolic alterations that underlie these diseases are reviewed. Their possible pathophysiological mechanisms and the functions played by sphingolipids one can deduce from these conditions are discussed. This article is part of a Special Issue entitled Brain Lipids.
Keywords	brain ; ceramides ; enzyme deficiencies ; enzymes ; gene targeting ; genes ; humans ; metabolism ; mice ; mutation ; nervous system diseases ; neurons
Language	English
Dates of publication	2015-08
Size	p. 1040-1051.
Publishing place	Elsevier B.V.
Document type	Article
ISSN	1388-1981
DOI	10.1016/j.bbalip.2015.01.010
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The Tricyclodecan-9-yl-xanthogenate D609 Triggers Ceramide Increase and Enhances FasL-Induced Caspase-Dependent and -Independent Cell Death in T Lymphocytes

Bruno Ségui / Thierry Levade / Hervé Benoist / Delphine Milhas / Nathalie Andrieu-Abadie

International Journal of Molecular Sciences, Vol 13, Iss 7, Pp 8834-

2012 Volume 8852

Abstract: D609 is known to modulate death receptor-induced ceramide generation and cell death. We show that in Jurkat cells, non-toxic D609 concentrations inhibit sphingomyelin synthase and, to a lesser extent, glucosylceramide synthase, and transiently increase ... ...

Abstract	D609 is known to modulate death receptor-induced ceramide generation and cell death. We show that in Jurkat cells, non-toxic D609 concentrations inhibit sphingomyelin synthase and, to a lesser extent, glucosylceramide synthase, and transiently increase the intracellular ceramide level. D609 significantly enhanced FasL-induced caspase activation and apoptosis. D609 stimulated FasL-induced cell death in caspase-8-deficient Jurkat cells, indicating that D609 acts downstream of caspase-8. At high FasL concentration (500 ng/mL), cell death was significantly, but not completely, inhibited by zVAD-fmk, a broad-spectrum caspase inhibitor, indicating that FasL can activate both caspase-dependent and -independent cell death signaling pathways. FasL-induced caspase activation was abolished by zVAD-fmk, whereas ceramide production was only partially impaired. D609 enhanced caspase-independent ceramide increase and cell death in response to FasL. Also, D609 overcame zVAD-fmk-conferred resistance to a FasL concentration as low as 50 ng/mL and bypassed RIP deficiency. It is likely that mitochondrial events were involved, since Bcl-xL over-expression impaired D609 effects. In PHA-activated human T lymphocytes, D609 enhanced FasL-induced cell death in the presence or absence of zVAD-fmk. Altogether, our data strongly indicate that the inhibition of ceramide conversion to complex sphingolipids by D609 is accompanied by an enhancement of FasL-induced caspase-dependent and -independent cell death in T lymphocytes.
Keywords	CD95 ; apoptosis ; necrosis ; sphingomyelin synthase ; glucosylceramide synthase ; ALPS ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2012-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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