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Inhibition of Neuronal Mitochondrial Complex I or Lysosomal Glucocerebrosidase is associated with Increased Dopamine and Serotonin Turnover

De La Fuente Barrigon, C; Burke, D; Eaton, SJ; Heales, S; (2017) Inhibition of Neuronal Mitochondrial Complex I or Lysosomal Glucocerebrosidase is associated with Increased Dopamine and Serotonin Turnover. Neurochemistry International , 109 pp. 94-100. 10.1016/j.neuint.2017.02.013. Green open access

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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.

Type: Article
Title: Inhibition of Neuronal Mitochondrial Complex I or Lysosomal Glucocerebrosidase is associated with Increased Dopamine and Serotonin Turnover
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neuint.2017.02.013
Publisher version: http://dx.doi.org/10.1016/j.neuint.2017.02.013
Language: English
Additional information: © 2016. This manuscript version is published under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International licence (CC BY-NC-ND 4.0). This licence allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licences are available at http://creativecommons.org/licenses/by/4.0. Access may be initially restricted by the publisher.
Keywords: Parkinson disease; Complex I; Glucocerebrosidase; Dopamine metabolism; Monoamine oxidase (maximum 6)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1542462
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