title: The contribution of mutant GBA to the development of Parkinson disease in Drosophila.
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.
authors.affiliation: Department of Cell Research and Immunology.
authors.forename: Gali
authors.initials: G
authors.lastname: Maor
authors.affiliation: Department of Cell Research and Immunology.
authors.forename: Or
authors.initials: O
authors.lastname: Cabasso
authors.affiliation: Department of Cell Research and Immunology.
authors.forename: Olga
authors.initials: O
authors.lastname: Krivoruk
authors.affiliation: Strang Laboratory of Cancer Research, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: Strang Laboratory of Cancer Research, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
authors.forename: Hermann
authors.initials: H
authors.lastname: Steller
authors.affiliation: Department of Molecular Microbiology and Biotechnology.|Sagol Interdisciplinary School of Neurosciences, Tel Aviv University, Tel Aviv, 69978, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Segal
authors.affiliation: Department of Cell Research and Immunology horwitzm@post.tau.ac.il.
authors.forename: Mia
authors.initials: M
authors.lastname: Horowitz
mesh_terms: D000551:Ambroxol / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005776:Gaucher Disease / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology
chemical_list: D000551:Ambroxol; D005962:Glucosylceramidase