Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish.

Lelieveld, Lindsey T.; Gerhardt, Sophie; Maas, Saskia; Zwiers, Kimberley C.; Wit, Claire de; Beijk, Ernst H.; Ferraz, Maria J.; Artola, Marta; Meijer, Annemarie H.; Tudorache, Christian; Salvatori, Daniela; Boot, Rolf G.; Aerts, Johannes M. F. G.

doi:10.1016/j.jlr.2022.100199

Cited by 11 publications

(17 citation statements)

References 76 publications

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“…The gba1-asahb1 double mutants did not accumulate glucosylsphingosine, as shown before (Fig. 5 B ) (24). Importantly, they lost resistance to Mm (Fig.…”

Section: Resultssupporting

confidence: 84%

“…1 E ). gba1 sa1621 homozygotes grew into early adulthood but were smaller in size and had curved spines that were previously reported for other zebrafish gba1 mutants, recapitulating the growth retardation and kyphosis seen in many Gaucher disease patients (19, 20, 24, 34) (Fig. 1 F ).…”

Section: Resultssupporting

confidence: 77%

“…The use of activity-based probes and mass spectrometric techniques have enabled the detailed biochemical assays to confirm in the zebrafish Gaucher disease model the metabolic shifts seen in human Gaucher disease (21). Importantly, the use of the zebrafish model has enabled the clarification of the role of the two glucocerebrosidases GBA1 (lysosomal facing) and GBA2 (cytosolic facing) and the downstream enzyme lysosomal acid ceramidase in lipid accumulation and disease phenotypes (21, 24).…”

Section: Introductionmentioning

confidence: 99%

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Gaucher Disease Protects Against Tuberculosis

Fan

Halre

Lelieveld

et al. 2022

Preprint

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Biallelic mutations in the glucocerebrosidase (GBA1) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. This and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.

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“…The gba1-asahb1 double mutants did not accumulate glucosylsphingosine, as shown before (Fig. 5 B ) (24). Importantly, they lost resistance to Mm (Fig.…”

Section: Resultssupporting

confidence: 84%

Section: Resultssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gaucher Disease Protects Against Tuberculosis

Fan

Halre

Lelieveld

et al. 2022

Preprint

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“…To elucidate the specific role of GlcSph in inflammation (and neuroinflammation in particular), experiments were conducted using a Gaucher zebrafish model where the expression of acid ceramidase, the enzyme responsible for GlcSph production, was ablated. This manipulation caused no reduction in the expression of inflammatory cytokines such as IL-1β and TNFβ in the brain [139], suggesting the minor contribution of GlcSph to the neuroinflammation in this model.…”

Section: Lysosphingolipids and "Tumor Promoting Inflammation/avoiding...mentioning

confidence: 82%

Potential Role of Sphingolipidoses-Associated Lysosphingolipids in Cancer

Dubot

Astudillo

Therville

et al. 2022

Cancers

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Sphingolipids play a key structural role in cellular membranes and/or act as signaling molecules. Inherited defects of their catabolism lead to lysosomal storage diseases called sphingolipidoses. Although progress has been made toward a better understanding of their pathophysiology, several issues still remain unsolved. In particular, whether lysosphingolipids, the deacylated form of sphingolipids, both of which accumulate in these diseases, are simple biomarkers or play an instrumental role is unclear. In the meanwhile, evidence has been provided for a high risk of developing malignancies in patients affected with Gaucher disease, the most common sphingolipidosis. This article aims at analyzing the potential involvement of lysosphingolipids in cancer. Knowledge about lysosphingolipids in the context of lysosomal storage diseases is summarized. Available data on the nature and prevalence of cancers in patients affected with sphingolipidoses are also reviewed. Then, studies investigating the biological effects of lysosphingolipids toward pro or antitumor pathways are discussed. Finally, original findings exploring the role of glucosylsphingosine in the development of melanoma are presented. While this lysosphingolipid may behave like a protumorigenic agent, further investigations in appropriate models are needed to elucidate the role of these peculiar lipids, not only in sphingolipidoses but also in malignant diseases in general.

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“…Thirty years ago, it was recognized that there was a very limited understanding of the full clinical spectrum and natural history of rare LSDs, such as Gaucher disease (GD). GD is caused by biallelic pathogenic variants in the GBA1 gene that underlie defective lysosomal glucocerebrosidase and toxic accumulation of beta-glucosylceramide and its bioactive metabolite, glucosylsphingosine [ 7 , 8 ]. In 1991, GD type 1 (GD1) was the first LSD to be treated using macrophage-targeted enzyme replacement therapy (ERT) alglucerase [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Rare lysosomal disease registries: lessons learned over three decades of real-world evidence

Mistry

Kishnani

Wanner

et al. 2022

Orphanet J Rare Dis

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Lysosomal storage disorders (LSD) are rare diseases, caused by inherited deficiencies of lysosomal enzymes/transporters, that affect 1 in 7000 to 1 in 8000 newborns. Individuals with LSDs face long diagnostic journeys during which debilitating and life-threatening events can occur. Clinical trials and classical descriptions of LSDs typically focus on common manifestations, which are not representative of the vast phenotypic heterogeneity encountered in real-world experience. Additionally, recognizing that there was a limited understanding of the natural history, disease progression, and real-world clinical outcomes of rare LSDs, a collaborative partnership was pioneered 30 years ago to address these gaps. The Rare Disease Registries (RDR) (for Gaucher, Fabry, Mucopolysaccharidosis type I, and Pompe), represent the largest observational database for these LSDs. Over the past thirty years, data from the RDRs have helped to inform scientific understanding and the development of comprehensive monitoring and treatment guidelines by creating a framework for data collection and establishing a standard of care, with an overarching goal to improve the quality of life of affected patients. Here, we highlight the history, process, and impact of the RDRs, and discuss the lessons learned and future directions.

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Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish.

Cited by 11 publications

References 76 publications

Gaucher Disease Protects Against Tuberculosis

Gaucher Disease Protects Against Tuberculosis

Potential Role of Sphingolipidoses-Associated Lysosphingolipids in Cancer

Rare lysosomal disease registries: lessons learned over three decades of real-world evidence

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