ArticleProceedings of the National Academy of Sciences of the United States of America2014
Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 3 of them syntheses that pooled it.
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Who cites it
57 citing papers in PubMed, 3 syntheses or guidelines pooled it, 108 citations in OpenAlex.
- Sphingolipids in Gaucher disease: a systematic review.Orphanet journal of rare diseases · 2025Pooled it
- Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review.International journal of molecular sciences · 2020Pooled it
- Emerging links between pediatric lysosomal storage diseases and adult parkinsonism.Movement disorders : official journal of the Movement Disorder Society · 2019Pooled it
- Assessment of Target Engagement in a First-in-Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders.Clinical and translational science · 2021Trial
- New insights into bone pathology through a transcriptomic profiling of an osteoblast model of Gaucher disease.Molecular genetics and metabolism reports · 2026Article
- Sphingolipidoses: expanding the spectrum of α-synucleinopathies.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- PPa1 insufficiency drives lysosomal storage disease and inflammatory macrophage expansion in the bone marrow.bioRxiv : the preprint server for biology · 2026Article
- Sinbaglustat is efficacious in GM2 gangliosidosis primarily through inhibition of GBA2 rather than GCS.Molecular therapy. Advances · 2026Article
- Glucosylsphingosine (Lyso-Gb1): An Update on Its Use as a Biomarker in Gaucher Disease.International journal of molecular sciences · 2026Review
- Refining Mouse Models of Gaucher Disease: Advancing Mechanistic Insights, Biomarker Discovery, and Therapeutic Strategies.International journal of molecular sciences · 2025Review
- Gaucher disease, state of the art and perspectives.Journal of internal medicine · 2025Review
- Deciphering metabolic shifts in Gaucher disease type 1: a multi-omics study.Journal of molecular medicine (Berlin, Germany) · 2025Article
- Cost-effectiveness analysis of ambroxol for the treatment of Chinese patients with Gaucher disease.Frontiers in medicine · 2025Article
- Deletion of Gba in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model.JCI insight · 2024Article
- Gaucher disease provides a unique window into Parkinson disease pathogenesis.Nature reviews. Neurology · 2024Review
- A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach.International journal of biological sciences · 2024Review
- Animal Models for the Study of Gaucher Disease.International journal of molecular sciences · 2023Review
- Zebra-Sphinx: Modeling Sphingolipidoses in Zebrafish.International journal of molecular sciences · 2023Review
- Article
- Gaucher disease - more than just a rare lipid storage disease.Journal of molecular medicine (Berlin, Germany) · 2022Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
The inherited deficiency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD). A vast majority of patients present with nonneuronopathic, type 1 GD (GD1). GBA deficiency causes the accumulation of two key sphingolipids, glucosylceramide (GL-1) and glucosylsphingosine (LysoGL-1), classically noted within the lysosomes of mononuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 pathophysiology is not known. We recently recapitulated hepatosplenomegaly, cytopenia, hypercytokinemia, and the bone-formation defect of human GD1 through conditional deletion of Gba in Mx1-Cre(+):GD1 mice. Here we show that the deletion of Gba2 significantly rescues the GD1 clinical phenotype, despite enhanced elevations in GL-1 and LysoGL-1. Most notably, the reduced bone volume and bone formation rate are normalized. These results suggest that metabolism of GL-1 or LysoGL-1 into downstream bioactive lipids is a major contributor to the bone-formation defect. Direct testing revealed a strong inhibition of osteoblast viability by nanomolar concentrations of sphingosine, but not of ceramide. These findings are consistent with toxicity of high circulating sphingosine levels in GD1 patients, which decline upon enzyme-replacement therapy; serum ceramide levels remain unchanged. Together, complementary results from mice and humans affected with GD1 not only pinpoint sphingosine as being an osteoblast toxin, but also set forth Gba2 as a viable therapeutic target for the development of inhibitors to ameliorate certain disabling consequences of GD1.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.