ArticleHuman molecular genetics2016
The contribution of mutant GBA to the development of Parkinson disease in Drosophila.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 73 citations in OpenAlex.
- The dual impact of GBA1 in disease: from germline mutations in neurological disorders to alterations in cancer.Cell death discovery · 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
- Exploring the versatility ofFly · 2025Review
- GBA1 Gene-Associated Transcriptomic Signatures Reveal Risk Genes in Parkinson's Disease.Biomedicines · 2025Article
- The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease.Human molecular genetics · 2025Article
- Bidirectional regulation of glycoprotein nonmetastatic melanoma protein B by β-glucocerebrosidase deficiency inbioRxiv : the preprint server for biology · 2025Article
- Prodromal Parkinsonian Features in Carriers of Gaucher Disease Compared to Controls.Life (Basel, Switzerland) · 2025Article
- Sidransky Syndrome-International journal of molecular sciences · 2025Review
- Drug Repositioning and Repurposing for Disease-Modifying Effects in Parkinson's Disease.Journal of movement disorders · 2025Article
- Electric-field induced sleep promotion and lifespan extension in Gaucher's disease model flies.Biochemistry and biophysics reports · 2025Article
- Current opinion on pluripotent stem cell technology in Gaucher's disease: challenges and future prospects.Cytotechnology · 2025Review
- Mass spectrometry-based proteomics for biomarker discovery in theNeuroprotection (Chichester, England) · 2024Review
- Functional Analysis of HumanCells · 2024Article
- Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease.Translational neurodegeneration · 2024Review
- Gaucher disease provides a unique window into Parkinson disease pathogenesis.Nature reviews. Neurology · 2024Review
- Review
- Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician's Perspective.Brain sciences · 2024Review
- Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease.PLoS genetics · 2023Article
- Animal models of Parkinson's disease: bridging the gap between disease hallmarks and research questions.Translational neurodegeneration · 2023Review
- Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease.Human molecular genetics · 2023Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Gaucher disease (GD) results from mutations in the acid β-glucocerebrosidase (GCase) encoding gene, GBA, which leads to accumulation of glucosylceramides. GD patients and carriers of GD mutations have a significantly higher propensity to develop Parkinson disease (PD) in comparison to the non-GD population. In this study, we used the fruit fly Drosophila melanogaster to show that development of PD in carriers of GD mutations results from the presence of mutant GBA alleles. Drosophila has two GBA orthologs (CG31148 and CG31414), each of which has a minos insertion, which creates C-terminal deletion in the encoded GCase. Flies double heterozygous for the endogenous mutant GBA orthologs presented Unfolded Protein Response (UPR) and developed parkinsonian signs, manifested by death of dopaminergic cells, defective locomotion and a shorter life span. We also established transgenic flies carrying the mutant human N370S, L444P and the 84GG variants. UPR activation and development of parkinsonian signs could be recapitulated in flies expressing these three mutant variants.UPR and parkinsonian signs could be partially rescued by growing the double heterozygous flies, or flies expressing the N370S or the L444P human mutant GCase variants, in the presence of the pharmacological chaperone ambroxol, which binds and removes mutant GCase from the endoplasmic reticulum (ER). However flies expressing the 84GG mutant, that does not express mature GCase, did not exhibit rescue by ambroxol. Our results strongly suggest that the presence of a mutant GBA allele in dopaminergic cells leads to ER stress and to their death, and contributes to development of PD.
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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.