title: Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE). Dopamine, its principal metabolites, and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the extracellular medium were quantified by HPLC. Inhibition of complex I significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA. Comparable results were observed with CBE. These results suggest increased monoamine oxidase activity and provide evidence for involvement of impaired complex I or GBA1 activity in the dopamine/serotonin deficiency seen in PD. Use of extracellular media may also permit relatively rapid assessment of dopamine/serotonin metabolism and permit screening of novel therapeutic agents.
authors.affiliation: ICH Centre for Translational Omics, Genetic and Genomic Medicine Development Bio & Cancer Programme, UCL GOS Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Electronic address: c.barrign@ucl.ac.uk.
authors.forename: Carmen
authors.initials: C
authors.lastname: de la Fuente
authors.affiliation: ICH Centre for Translational Omics, Genetic and Genomic Medicine Development Bio & Cancer Programme, UCL GOS Institute of Child Health and Chemical Pathology, Great Ormond Street Hospital, London, WC1N 3JH, UK. Electronic address: derek.burke@gosh.nhs.uk.
authors.forename: Derek G
authors.initials: DG
authors.lastname: Burke
authors.affiliation: ICH Development Biology and Cancer Programme, UCL GOS Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Electronic address: s.eaton@ucl.ac.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Eaton
authors.affiliation: ICH Centre for Translational Omics, Genetic and Genomic Medicine Development Bio & Cancer Programme, UCL GOS Institute of Child Health and Chemical Pathology, Great Ormond Street Hospital, London, WC1N 3JH, UK. Electronic address: s.heales@ucl.ac.uk.
authors.forename: Simon J R
authors.initials: SJR
authors.lastname: Heales
mesh_terms: D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D012701:Serotonin; D007294:Inositol; D005962:Glucosylceramidase; D042967:Electron Transport Complex I; C011423:conduritol epoxide; D004298:Dopamine
keywords: 3-OMD (PubChem CID: 38853); 5-HIAA (PubChem CID: 1826); Complex I; DOPAC (PubChem CID: 547); Dopamine (PubChem CID: 681); Dopamine metabolism; Glucocerebrosidase; HVA (PubChem CID: 1738); Monoamine oxidase; Parkinson disease