title: Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage.
abstract: Mutations of the gene for glucocerebrosidase 1 (GBA) cause Gaucher disease (GD), an autosomal recessive lysosomal storage disorder. Individuals with homozygous or heterozygous (carrier) mutations of GBA have a significantly increased risk for the development of Parkinson's disease (PD), with clinical and pathological features that mirror the sporadic disease. The mechanisms whereby GBA mutations induce dopaminergic cell death and Lewy body formation are unknown. There is evidence of mitochondrial dysfunction and oxidative stress in PD and so we have investigated the impact of glucocerebrosidase (GCase) inhibition on these parameters to determine if there may be a relationship of GBA loss-of-function mutations to the known pathogenetic pathways in PD. We have used exposure to a specific inhibitor (conduritol-β-epoxide, CβE) of GCase activity in a human dopaminergic cell line to identify the biochemical abnormalities that follow GCase inhibition. We show that GCase inhibition leads to decreased ADP phosphorylation, reduced mitochondrial membrane potential and increased free radical formation and damage, together with accumulation of alpha-synuclein. Taken together, inhibition of GCase by CβE induces abnormalities in mitochondrial function and oxidative stress in our cell culture model. We suggest that GBA mutations and reduced GCase activity may increase the risk for PD by inducing these same abnormalities in PD brain.
authors.affiliation: Department of Clinical Neurosciences, University College London Institute of Neurology, United Kingdom.
authors.forename: Michael W J
authors.initials: MW
authors.lastname: Cleeter
authors.forename: Kai-Yin
authors.initials: KY
authors.lastname: Chau
authors.forename: Caroline
authors.initials: C
authors.lastname: Gluck
authors.forename: Atul
authors.initials: A
authors.lastname: Mehta
authors.forename: Derralynn A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Michael
authors.initials: M
authors.lastname: Duchen
authors.forename: Nicholas William
authors.initials: NW
authors.lastname: Wood
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: J
authors.initials: J
authors.lastname: Mark Cooper
authors.forename: Anthony Henry
authors.initials: AH
authors.lastname: Schapira
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D015153:Blotting, Western; D002460:Cell Line; D004579:Electron Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000633:toxicity*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007202:Indicators and Reagents; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005609:Free Radicals; D007202:Indicators and Reagents; D025801:Ubiquitin; D007294:Inositol; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005962:Glucosylceramidase; D046988:Proteasome Endopeptidase Complex; C011423:conduritol epoxide