title: Glucocerebrosidase deficiency and mitochondrial impairment in experimental Parkinson disease.
abstract: Gaucher disease is an autosomal recessive disease, caused by a lack or functional deficiency of the lysosomal enzyme, glucocerebrosidase (GCase). Recently, mutations in the glucocerebrosidase gene (GBA) have been associated with Parkinson's disease (PD) and GBA mutations are now considered the most important genetic vulnerability factor for PD. In this study, we have investigated (i) in vivo whether inhibition of the enzyme glucosylceramide synthase by miglustat may protect C57Bl/6 mice against subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication and (ii) in vitro whether a decrease of GCase activity may render dopaminergic neurons susceptible to MPP(+) (1-methyl-4-phenylpyridinium) or alpha-synuclein (α-Syn) toxicity and amenable to miglustat treatment. We could demonstrate that reduction of glucocerebroside by inhibition of glucosylceramide synthase partially protects mice against MPTP-induced toxicity. Conversely, we could show that inhibition of GCase activity with conduritol-B-epoxide (CBE) enhances both α-Syn and MPP(+) induced toxicity in vitro. However, only CBE-induced enhancement of MPP(+) toxicity could be reversed by miglustat. Moreover, we were unable to reveal any alterations of complex I activity or cell respiration upon treatment with either CBE or miglustat. Our findings suggest that the reduction of GCase activity rather than an accumulation of glucocerebroside increases aSyn toxicity.
authors.affiliation: INSERM, CR-ICM, UMR_S1127, 75013 Paris, France; Université Pierre et Marie Curie Paris 06, UMR_S975, 75013 Paris France; CNRS, UMR 7225, CR-ICM, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Department of Neurology, Faculty of Medicine, Philipps-University, Marburg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Noelker
authors.affiliation: INSERM, CR-ICM, UMR_S1127, 75013 Paris, France; Université Pierre et Marie Curie Paris 06, UMR_S975, 75013 Paris France; CNRS, UMR 7225, CR-ICM, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Lixia
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Neurology, Faculty of Medicine, Philipps-University, Marburg, Germany; Department of Neurology, Technical University, Munich, Germany.; Deptartment of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Höllerhage
authors.affiliation: Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Franca
authors.initials: F
authors.lastname: Vulinovic
authors.affiliation: Department of Neurology, Faculty of Medicine, Philipps-University, Marburg, Germany.
authors.forename: Annekathrin
authors.initials: A
authors.lastname: Sturn
authors.affiliation: Actelion Pharmaceuticals Ltd, 4123 Allschwil, Switzerland.
authors.forename: René
authors.initials: R
authors.lastname: Roscher
authors.affiliation: Department of Neurology, Faculty of Medicine, Philipps-University, Marburg, Germany; Department of Neurology, Technical University, Munich, Germany.; Deptartment of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
authors.affiliation: INSERM, CR-ICM, UMR_S1127, 75013 Paris, France; Université Pierre et Marie Curie Paris 06, UMR_S975, 75013 Paris France; CNRS, UMR 7225, CR-ICM, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.affiliation: Department of Neurology, Faculty of Medicine, Philipps-University, Marburg, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.affiliation: INSERM, CR-ICM, UMR_S1127, 75013 Paris, France; Université Pierre et Marie Curie Paris 06, UMR_S975, 75013 Paris France; CNRS, UMR 7225, CR-ICM, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany; Department of Psychiatry, University of Luebeck, 23562 Luebeck, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alvarez-Fischer
authors.affiliation: INSERM, CR-ICM, UMR_S1127, 75013 Paris, France; Université Pierre et Marie Curie Paris 06, UMR_S975, 75013 Paris France; CNRS, UMR 7225, CR-ICM, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France. Electronic address: andreas.hartmann@psl.aphp.fr.
authors.forename: Hartmann
authors.initials: H
authors.lastname: Andreas
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005776:Gaucher Disease / Q000188:drug therapy / Q000209:etiology* / Q000517:prevention & control; D065089:Glycoside Hydrolase Inhibitors / Q000627:therapeutic use; D006649:Histocompatibility Antigens / Q000378:metabolism; D007294:Inositol / Q000031:analogs & derivatives / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D028361:Mitochondrial Diseases / Q000209:etiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000150:complications* / Q000517:prevention & control; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D006649:Histocompatibility Antigens; D017485:1-Deoxynojirimycin; D007294:Inositol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C059896:miglustat; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; C011423:conduritol epoxide
keywords: Dopamine cell death; Gaucher disease; Glucocerebrosidase; MPTP; Mitochondria; Parkinson's disease; α-Syn