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Dopamine and Serotonin Metabolism in Parkinsonian Models

De La Fuente Barrigon, C; (2018) Dopamine and Serotonin Metabolism in Parkinsonian Models. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra. Different pathogenic mechanisms have been implicated, including loss of mitochondrial complex I function and dysfunction of lysosomal glucocerebrosidase (GBA1) (Neumann et al., 2009; Schapira et al., 1990). Also, it has been hypothesised that serotonin metabolism could be affected in these patients due to the number of enzymes shared by both pathways (Albizu et al., 2011). This thesis considers the potential involvement of complex I and GBA1 in PD using HPLC analysis of changes in the extracellular levels of the metabolites of dopamine and serotonin, and the expression and activity of the enzymes of the dopamine pathway. Using SH-SY5Y cells, complex I deficiency was modelled using rotenone, and GBA1 deficiency was modelled using conduritol B epoxide (CBE). Inhibition of mitochondrial complex I or GBA1 significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), direct products of the degradation by monoamine oxidase (MAO) of dopamine and serotonin respectively. These results suggest increased MAO activity, providing evidence for the involvement of impaired complex I or GBA1 activity in the dopamine deficiency seen in PD. As MAO produces hydrogen peroxide as a side-product, its increased activity could enhance the oxidative stress present in PD (Dias et al., 2013). Therefore, intracellular GSH levels were quantified to determine whether the antioxidant mechanisms were affected, but no changes were observed. In addition to the main project, I collaborated with a number of groups to study monoamine metabolism in parkinsonian models. Also, the glycoprofile of cerebrospinal fluid (CSF) of patients with and without impaired dopamine metabolism was studied to explore the possibility of using glycans as pathologic biomarkers.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Dopamine and Serotonin Metabolism in Parkinsonian Models
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Dopamine, HPLC, Parkinson's disease, Mitochondria, Lysosome, Complex I, Glucocerebrosidase.
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10054116
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