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Int. J. Mol. Sci. 2017, 18(10), 2192; doi:10.3390/ijms18102192

Glucosylsphingosine Causes Hematological and Visceral Changes in Mice—Evidence for a Pathophysiological Role in Gaucher Disease

Albrecht-Kossel Institute of the Rostock University Medical Center, 18147 Rostock, Germany
Centogene AG, 18057 Rostock, Germany
Department of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany
Institute for Medical Psychology and Medical Sociology, Rostock University Medical Center, 18147 Rostock, Germany
Author to whom correspondence should be addressed.
Received: 8 September 2017 / Revised: 26 September 2017 / Accepted: 9 October 2017 / Published: 20 October 2017
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
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Glucosylceramide and glucosylsphingosine are the two major storage products in Gaucher disease (GD), an inherited metabolic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The build-up of glucosylceramide in the endoplasmic reticulum and prominent accumulation in cell lysosomes of tissue macrophages results in decreased blood cell and platelet counts, and skeletal abnormalities. The pathological role of the deacylated form of glucosylceramide, glucosylsphingosine (lyso-Gb1), a recently identified sensitive and specific biomarker for GD, is not well investigated. We established a long-term infusion model in C57BL/6JRj mice to examine the effect of lyso-Gb1 on representative hallmark parameters of GD. Mice received lyso-Gb1 at a dosage of 10 mg·kg−1 per day as a continuous subcutaneous administration, and were routinely checked for blood lyso-Gb1 levels using liquid chromatography-multiple reaction monitoring mass spectrometry (LC/MRM-MS) measurements at four-weekly intervals throughout treatment. The C57BL/6JRj mice showed a stable increase of lyso-Gb1 up to->500-fold greater than the normal reflecting concentrations seen in moderately to severely affected patients. Furthermore, lyso-Gb1 accumulated in peripheral tissues. The mice developed hematological symptoms such as reduced hemoglobin and hematocrit, increased spleen weights and a slight inflammatory tissue response after eight weeks of treatment. The above findings indicate a measurable visceral and hematological response in treated mice that suggests a role for lyso-Gb1 in the development of peripheral signs of GD. View Full-Text
Keywords: sphingolipids; glucocerebrosidase; biomarker; storage disease pathology; chemically-induced phenotype sphingolipids; glucocerebrosidase; biomarker; storage disease pathology; chemically-induced phenotype

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Lukas, J.; Cozma, C.; Yang, F.; Kramp, G.; Meyer, A.; Neßlauer, A.-M.; Eichler, S.; Böttcher, T.; Witt, M.; Bräuer, A.U.; Kropp, P.; Rolfs, A. Glucosylsphingosine Causes Hematological and Visceral Changes in Mice—Evidence for a Pathophysiological Role in Gaucher Disease. Int. J. Mol. Sci. 2017, 18, 2192.

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