ArticleHuman molecular genetics2018
Acid ceramidase inhibition ameliorates α-synuclein accumulation upon loss of GBA1 function.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 2 of them syntheses that pooled it.
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Who cites it
54 citing papers in PubMed, 2 syntheses or guidelines pooled it, 74 citations in OpenAlex.
- Sphingolipids in Gaucher disease: a systematic review.Orphanet journal of rare diseases · 2025Pooled it
- Emerging links between pediatric lysosomal storage diseases and adult parkinsonism.Movement disorders : official journal of the Movement Disorder Society · 2019Pooled it
- Review
- Sphingolipidoses: expanding the spectrum of α-synucleinopathies.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Glucosylceramide-induced ectosomes propagate pathogenic α-synuclein in Parkinson's disease.Nature cell biology · 2026Article
- Acid sphingomyelinase inhibition restores RPE homeostasis and photoreceptor function in preclinical Stargardt macular degeneration models.bioRxiv : the preprint server for biology · 2026Article
- Multi-omics insights into GBA1-associated Parkinson's disease: interplay of genomics, transcriptomics, proteomics, and lipidomics.Molecular neurodegeneration · 2026Review
- Inhibition or genetic reduction of ASAH1/acid ceramidase restore α-synuclein clearance in mutant GBA1 dopamine neurons from Parkinson's patients.Human molecular genetics · 2025Article
- Synaptic and cognitive impairment associated with L444P heterozygous glucocerebrosidase mutation.Brain : a journal of neurology · 2025Article
- Lysophosphatidylcholine promoting α-Synuclein aggregation in Parkinson's disease: disrupting GCase glycosylation and lysosomal α-Synuclein degradation.NPJ Parkinson's disease · 2025Article
- CoPPIs algorithm: a tool to unravel protein cooperative strategies in pathophysiological conditions.Briefings in bioinformatics · 2025Article
- Interactions of alpha-synuclein with membranes in Parkinson's disease: Mechanisms and therapeutic strategies.Neurobiology of disease · 2024Review
- Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.Cellular and molecular life sciences : CMLS · 2024Review
- Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies.Metabolites · 2024Review
- Peripheral Upregulation of Parkinson's Disease-Associated Genes Encoding α-Synuclein, β-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression.International journal of molecular sciences · 2024Article
- Inhibition of cysteine protease cathepsin L increases the level and activity of lysosomal glucocerebrosidase.JCI insight · 2024Article
- Article
- Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin.Frontiers in neuroscience · 2024Article
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.Disease models & mechanisms · 2023Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
GBA1 encodes the lysosomal enzyme β-glucocerebrosidase (GCase) which converts glucosylceramide into ceramide and glucose. Mutations in GBA1 lead to Gaucher's disease and are a major risk factor for Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), synucleinopathies characterized by accumulation of intracellular α-synuclein. In this study, we examined whether decreased ceramide that is observed in GCase-deficient cells contributes to α-synuclein accumulation. We demonstrated that deficiency of GCase leads to a reduction of C18-ceramide species and altered intracellular localization of Rab8a, a small GTPase implicated in secretory autophagy, that contributed to impaired secretion of α-synuclein and accumulation of intracellular α-synuclein. This secretory defect was rescued by exogenous C18-ceramide or chemical inhibition of lysosomal enzyme acid ceramidase that converts lysosomal ceramide into sphingosine. Inhibition of acid ceramidase by carmofur resulted in increased ceramide levels and decreased glucosylsphingosine levels in GCase-deficient cells, and also reduced oxidized α-synuclein and levels of ubiquitinated proteins in GBA1-PD patient-derived dopaminergic neurons. Together, these results suggest that decreased ceramide generation via the catabolic lysosomal salvage pathway in GCase mutant cells contributes to α-synuclein accumulation, potentially due to impaired secretory autophagy. We thus propose that acid ceramidase inhibition which restores ceramide levels may be a potential therapeutic strategy to target synucleinopathies linked to GBA1 mutations including PD and DLB.
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