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

ABSTRACT: 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.

SUBMITTER: Lukas J

PROVIDER: S-EPMC5666873 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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

Lukas Jan J Cozma Claudia C Yang Fan F Kramp Guido G Meyer Anja A Neßlauer Anna-Maria AM Eichler Sabrina S Böttcher Tobias T Witt Martin M Bräuer Anja U AU Kropp Peter P Rolfs Arndt A

International journal of molecular sciences 20171020 10

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 (lys ...[more]

PMID: 29053611

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Project description:BACKGROUND: Gaucher disease (GD) is a rare recessively inherited disorder caused by deficiency of a lysosomal enzyme, glucocerebrosidase. Accumulation of glucosylceramide or glucosylsphingosine in macrophages leads to increased production of ferritin and chitotriosidase and to decreases in hemoglobin concentration and platelet count, which are used as blood biomarkers. GD is treated by enzyme replacement therapy (ERT) or, sometimes by substrate reduction therapy. However, no physiological model for analysis of biomarkers change during ERT has been proposed. We aimed to develop a pathophysiological model to analyze biomarker's response to ERT and several covariates impact. METHODS: Changes in blood ferritin, chitotriosidase, hemoglobin and platelets were analyzed in French GD Registry patients receiving imiglucerase/alglucerase as ERT. We used simplified exponential pathophysiological model, with initial concentration, biomarkers amplitude of variation and rate constant of normalization during ERT. Changes in four biomarkers were analyzed separately and then all four together from initiation to discontinuation of ERT, or until the end of follow-up. Several covariates were tested, including age at ERT initiation, splenectomy, sex, genotype (N370S/N370S), and ERT dose. RESULTS: An exponential model gave a good data fit. The four biomarkers analysis showed that the rate of nomalization was the same for all biomarkers, with a half-life of 0.5 years. Predicted values of biomarkers at ERT's steady state were 40% and 10% of initial concentrations, for ferritin and chitotriosidase, respectively, and 120% and 200% for hemoglobin and platelets, respectively. We found that 3 covariates had an effect on initial concentration or on amplitude of variation in ferritin, hemoglobin and platelets: women and patients under 15 years of age had lower ferritin and hemoglobin concentrations, and patients under 15 years of age had higher platelet count. Splenectomized patients had higher ferritin concentrations and platelet count and lower amplitude of variation of hemoglobin. CONCLUSION: We report the first dynamic model of biomarker changes in GD. It enabled us to estimate that 95% of biomarker response to ERT was achieved in 2 years, but with high inter-patient variability. We also found that with the current treatment, normalization of chitotriosidase and ferritin will occur in about 65% of patients.

Project description:Purpose: The goals of this study are to examine how maternal exposure to oxycodone affects the global transcriptome and histological structure of the mouse placenta at 12.5 dpc of pregnancy.retinal transcriptome profiling (RNA-seq) to microarray and quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods and to evaluate protocols for optimal high-throughput data analysis Methods: A high throughput RNA sequencing method was used to examine the global transcriptomic changes affected by oxycodone in male and female conceptuses. Histomorphometrics were used to assess the various regions of the placenta, namely the labyrinth, spongiotrophoblast, and parietal trophoblast giant cell (pTGC) region. The open-sourced software, weighted correlation network analysis (WGCNA) was used to link gene expression changes and histological (phenotypic) changes. Results: Using an optimized data analysis workflow, we mapped over 40 million sequence reads per sample to the mouse genome (build grcm38). An average of 95.6% of reads (38.7 million) was mapped with HISAT2 workflow. We identified 12,138 transcripts in the placenta of saline control and oxycodone mice with featureCounts workflow. One hundred eighty-eight transcripts showed differential expression between the OXY male vs. CTL male placenta, with a log2Foldchange ≥1 and p value <0.05. Fifty-eight transcripts showed differential expression between the OXY female vs. CTL female placenta, with a log2Foldchange ≥1 and p value <0.05. Hierarchical clustering of differentially expressed genes uncovered several genes that may contribute to placenta function. Conclusions: Our study represents the first detailed analysis of placental transcriptomes in oxycodone-exposed mice, with biologic replicates, generated by RNA-seq technology. The data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. We conclude that oxycodone exposure changed transcriptome characterization and these changes were associated with placenta histological features.

Project description:Alterations in the levels of serum sphingolipids and phospholipids have been reported in Gaucher disease and in Parkinson's disease, suggesting a potential role of these lipids as biomarkers. This project's objective is to detect novel associations and novel candidate biomarkers in the largest Spanish Gaucher and Parkinson diseases of the Iberian Peninsula. For that, 278 participants were included: 100 sporadic Parkinson's patients, 70 Gaucher patients, 15 GBA1-mutation-carrier Parkinson's patients and 93 controls. A serum lipidomics array including 10 phospholipid groups, 368 species, was performed using high-performance liquid chromatography-mass spectrometry. Lipid levels were compared between groups via multiple-regression analyses controlling for clinical and demographic parameters. Additionally, lipid levels were compared within the Gaucher and Parkinson's groups controlling for medication and/or disease severity. Results were controlled for robustness by filtering of non-detectable lipid values. There was an increase in the levels of phosphatidylcholine, with a simultaneous decrease in lyso-phosphatidylcholine, in the Gaucher, Parkinson's and GBA1-mutation-carrier Parkinson's patients vs. controls. Phosphatidylethanolamine, lyso- and plasmalogen-phosphatidylethanolamine were also increased in Gaucher and Parkinson's. Gaucher patients also showed an increase in lyso-phosphatidylserine and phosphatidylglycerol. While in the Gaucher and Parkinson's groups, velaglucerase alpha and dopamine agonists, respectively, showed positive associations with the lipid changes, miglustat treatment in Gaucher patients normalized the altered phosphatidylcholine/lyso-phosphatidylcholine ratio. In conclusion, Gaucher and Parkinson's patients showed changes in various serum phospholipid levels when compared with healthy controls, further supporting the role of such lipids in disease development and, possibly, as putative biomarkers. This hypothesis was reinforced by the normalizing effect of miglustat, and by controlling for data robustness, even though the limited number of participants, especially in the sub-distribution by treatment groups in GD requires validation in a larger number of patients.

Project description:ObjectiveIn Huntington's disease (HD), the disease-causing huntingtin (HTT) protein is ubiquitously expressed and causes both central and peripheral pathology. In clinical HD, a higher body mass index has been associated with slower disease progression, indicating the role of metabolic changes in disease pathogenesis. Underlying mechanisms of metabolic changes in HD remain poorly understood, but recent studies suggest the involvement of hypothalamic dysfunction. The present study aimed to investigate whether modulation of hypothalamic HTT levels would affect metabolic phenotype and disease features in HD using mouse models.MethodsWe used the R6/2 and BACHD mouse models that express different lengths of mutant HTT to develop lean- and obese phenotypes, respectively. We utilized adeno-associated viral vectors to overexpress either mutant or wild-type HTT in the hypothalamus of R6/2, BACHD, and their wild-type littermates. The metabolic phenotype was assessed by body weight measurements over time and body composition analysis using dual-energy x-ray absorptiometry at the endpoint. R6/2 mice were further characterized using behavioral analyses, including rotarod, nesting-, and hindlimb clasping tests during early- and late-time points of disease progression. Finally, gene expression analysis was performed in R6/2 mice and wild-type littermates in order to assess transcriptional changes in the hypothalamus and adipose tissue.ResultsHypothalamic overexpression of mutant HTT induced significant gender-affected body weight gain in all models, including wild-type mice. In R6/2 females, early weight gain shifted to weight loss during the corresponding late stage of disease despite increased fat accumulation. Body weight changes were accompanied by behavioral alterations. During the period of early weight gain, R6/2 mice displayed a comparable locomotor capacity to wild-type mice. When assessing behavior just prior to weight loss onset in R6/2 mice, decreased locomotor performance was observed in R6/2 females with hypothalamic overexpression of mutant HTT. Transcriptional downregulation of beta-3 adrenergic receptor (B3AR), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-gamma (PPARγ) in gonadal white adipose tissue was accompanied by distinct alterations in hypothalamic gene expression profiles in R6/2 females after mutant HTT overexpression. No significant effect on metabolic phenotype in R6/2 was seen in response to wild-type HTT overexpression.ConclusionsTaken together, our findings provide further support for the role of HTT in metabolic control via hypothalamic neurocircuits. Understanding the specific central neurocircuits and their peripheral link underlying metabolic imbalance in HD may open up avenues for novel therapeutic interventions.

Dataset Information

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

Publications

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

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