The origins of glucosylsphingosine in Gaucher disease

Flanagan, John J.; Ranes, Brian; Brignol, Nastry; Hamler, Rick; Clark, Spencer K.

doi:10.1016/j.ymgme.2012.11.087

Cited by 4 publications

(6 citation statements)

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“…For wild-type mice receiving CBE, approximate 40- and 400-fold increases were seen in GlcCer and GlcSph brain levels, respectively (Figure ), relative to untreated mice ( p < 0.05). These findings are consistent with a previous report, as well as with our earlier work showing that increased levels of GlcSph result from both increased production of GlcSph by acid ceramidase-mediated deacylation of GlcCer, and decreased metabolism of GlcCer due to GCase inhibition . However, results were quite different when wild-type mice were administered NB-DGJ (Figure ).…”

Section: Resultsmentioning

confidence: 84%

“…GBA2 is known to metabolize nonlysosomal GlcCer; however, it is unclear if GlcSph is a substrate for GBA2. Further, it has been shown that GlcCer is deacylated in lysosomes by acid ceramidase. − We used our recently developed methodologies to better understand the connection between these two sphingolipids in brain tissue taken from mice after administration of the GCase inhibitor conduritol β-epoxide (CBE), or with an inhibitor of nonlysosomal GBA2, N -butyl-deoxy-galactonojirimycin (NB-DGJ). In vitro studies have shown that CBE selectively inhibits GCase, − while NB-DGJ selectively inhibits GBA2. , …”

Section: Resultsmentioning

confidence: 99%

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Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease

et al. 2017

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Gaucher disease (GD) is caused by mutations in the GBA1 gene that encodes the lysosomal enzyme acid β-glucosidase (GCase). Reduced GCase activity primarily leads to the accumulation of two substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Current treatment options have not been shown to ameliorate the neurological pathology observed in the most severe forms of GD, clearly representing an unmet medical need. To better understand the relationship between GlcCer and GlcSph accumulation and ultimately their connection with the progression of neurological pathology, we developed LC-MS/MS methods to quantify GlcCer and GlcSph in mouse brain tissue. A significant challenge in developing these methods was the chromatographic separation of GlcCer and GlcSph from the far more abundant isobaric galactosyl epimers naturally occurring in white matter. After validation of both methods, we evaluated the levels of both substrates in five different GD mouse models, and found significant elevation of brain GlcSph in all five, while GlcCer was elevated in only one of the five models. In addition, we measured GlcCer and GlcSph levels in the brains of wild-type mice after administration of the GCase inhibitor conduritol β-epoxide (CBE), as well as the nonlysosomal β-glucosidase (GBA2) inhibitor N-butyldeoxygalactonojirimycin (NB-DGJ). Inhibition of GCase by CBE resulted in elevation of both sphingolipids; however, inhibition of GBA2 by NB-DGJ resulted in elevation of GlcCer only. Taken together, these data support the idea that GlcSph is a more selective and sensitive biomarker than GlcCer for neuronopathic GD in preclinical models.

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Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease

et al. 2017

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“…By causing the loss of, or a marked reduction in, the catalytic activity of GCase, these mutations are responsible for the lysosomal accumulation of undegraded GlcCer. Importantly, the lysosphingolipid molecule β-glucosylsphingosine (GlcSph) also accumulates [17], likely due to the cleavage of excess GlcCer by lysosomal ACDase [18,19]. The lipid storage mostly affects monocytic-macrophage cells (the so-called Gaucher cells) in the spleen, liver and bone marrow, but can also involve cells of the central nervous system in the most severe, neuronopathic form of the disease.…”

Section: Introduction: Glucosylceramide and Gaucher Diseasementioning

confidence: 99%

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

Dubot

Astudillo

Therville

et al. 2020

Cancers

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The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.

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“…Interestingly, a defect in glucosylceramidase 1 (GBA1) resulting in Gaucher inborn disorder (GD), owing to a defect in GlcCer hydrolysis into ceramide, is associated with an increased risk of malignancies, including melanoma [ 37 , 38 ]. Indeed, accumulation of GlcCer as well as glucosylsphingosine, which arises from the cleavage of excess GlcCer by AC [ 39 , 40 ], occurs in macrophages and could severely alter the immune and inflammatory responses. This could create a favourable microenvironment to promote melanomagenesis (for review see [ 38 ]).…”

Section: Role Of the Sphingolipid Metabolism In Melanomagenesismentioning

confidence: 99%

New Insights into the Role of Sphingolipid Metabolism in Melanoma

Carrié

Virazels

Dufau

et al. 2020

Cells

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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.

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The origins of glucosylsphingosine in Gaucher disease

Cited by 4 publications

References 0 publications

Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease

Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

New Insights into the Role of Sphingolipid Metabolism in Melanoma

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