ArticlePloS one2011
Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 72 citations in OpenAlex.
- Assessment of Target Engagement in a First-in-Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders.Clinical and translational science · 2021Trial
- Sinbaglustat is efficacious in GM2 gangliosidosis primarily through inhibition of GBA2 rather than GCS.Molecular therapy. Advances · 2026Article
- Therapeutic Effects of Nizubaglustat in a Mouse Model of GM2 Gangliosidosis.Journal of inherited metabolic disease · 2026Article
- Advances in Diagnosis, Pathological Mechanisms, Clinical Impact, and Future Therapeutic Perspectives in Tay-Sachs Disease.Neurology international · 2025Review
- Efficacy of Adeno-Associated Virus Serotype 9-Mediated Gene Therapy for AB-Variant GM2 Gangliosidosis.International journal of molecular sciences · 2023Article
- Rescue of lysosomal function as therapeutic strategy for SPG15 hereditary spastic paraplegia.Brain : a journal of neurology · 2023Article
- Plasma neurofilament light, glial fibrillary acidic protein and lysosphingolipid biomarkers for pharmacodynamics and disease monitoring of GM2 and GM1 gangliosidoses patients.Molecular genetics and metabolism reports · 2022Article
- Therapeutic Strategies For Tay-Sachs Disease.Frontiers in pharmacology · 2022Review
- GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies.International journal of molecular sciences · 2020Review
- Lipids in the Physiopathology of Hereditary Spastic Paraplegias.Frontiers in neuroscience · 2020Review
- Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson's disease.Molecular neurodegeneration · 2019Article
- Role of β-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish.Journal of lipid research · 2019Article
- mTOR hyperactivity mediates lysosomal dysfunction in Gaucher's disease iPSC-neuronal cells.Disease models & mechanisms · 2019Article
- Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Glycosphingolipids and Infection. Potential New Therapeutic Avenues.Frontiers in cell and developmental biology · 2019Review
- Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses.Journal of lipid research · 2018Article
- Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types.Human molecular genetics · 2018Article
- Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration.Cell reports · 2018Article
- N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV.Neurobiology of disease · 2017Article
- Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises.Frontiers in pharmacology · 2017Review
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.
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