title: Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models.
abstract: GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD. We treated fibroblast cells from PD patients with heterozygous GBA mutations and Drosophila expressing human wild-type, N370S and L444P GBA with the molecular chaperones ambroxol and isofagomine. Both chaperones increased GCase levels and activity, but also GBA mRNA, in control and mutant GBA fibroblasts. Expression of mutated GBA in Drosophila resulted in dopaminergic neuronal loss, a progressive locomotor defect, abnormal aggregates in the ER and increased levels of the ER stress reporter Xbp1-EGFP. Treatment with both chaperones lowered ER stress and prevented the loss of motor function, providing proof of principle that small molecule chaperones can reverse mutant GBA-mediated ER stress in vivo and might prove effective for treating PD.
authors.affiliation: Department of Biomedical Sciences, University of Sheffield, Sheffield, S10 2TN, UK.|Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Sanchez-Martinez
authors.affiliation: Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Beavan
authors.affiliation: Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Gegg
authors.affiliation: Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Kai-Yin
authors.initials: KY
authors.lastname: Chau
authors.affiliation: Department of Biomedical Sciences, University of Sheffield, Sheffield, S10 2TN, UK.|Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whitworth
authors.affiliation: Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PF, UK.
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
mesh_terms: D000551:Ambroxol / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D004331:Drosophila melanogaster / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D050112:Imino Pyranoses / Q000008:administration & dosage / Q000494:pharmacology; D018832:Molecular Chaperones / Q000008:administration & dosage* / Q000494:pharmacology; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D050112:Imino Pyranoses; D018832:Molecular Chaperones; C098432:isofagomine; D000551:Ambroxol; D005962:Glucosylceramidase