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Dopamine and Serotonin Metabolism in Parkinsonian Models Dopamine and Serotonin Metabolism in Parkinsonian Models Carmen de la Fuente Barrigon UCL Great Ormond Street Institute of Child Health Thesis submitted for the degree of Doctor of Philosophy (PhD) awarded by University College London (UCL). Funded by Marie Skłodowska-Curie Actions of the European Union’s Seventh Framework Programme (FP7). APRIL 2018 1 I, Carmen de la Fuente Barrigon confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed ………………………………………….. Date ……………………………………………… 3 Dedico esta tesis a los pilares de mi vida. A mis padres, Tomás y Marisa. A mi hermana, Paloma. A mi amor, Francesco. Por vuestros sacrificios, paciencia, amor y apoyo incondicionales que me hacen ser quien soy hoy. 5 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. 7 Impact statement This thesis has improved understanding in Parkinson’s Disease (PD) pathogenic mechanisms. This has been achieved by demonstrating a common effect on dopamine metabolism when mitochondria or lysosomes are affected in a cellular model. Parkinson’s disease (PD) is the second most common neurodegenerative disorder and it is caused by loss of dopaminergic neurons in the substantia nigra. Although different mechanisms have been implicated in the pathogenesis of PD, e.g. loss of mitochondrial complex I function, dysfunction of lysosomal glucocerebrosidase (GBA1), the triggering cause is still unknown. At UCL, a project called Training in Neurodegeneration, Therapeutics Intervention and Neurorepair (TINTIN) funded by Marie Curie Actions and European Union Seventh Framework Programme, aimed to research the relationship between two known organelles that are affected in PD and the cause of the disease symptoms, the loss of dopamine in the substantia nigra. To do so, changes in the release of dopamine and its metabolites by a cellular model were studied by high-performance liquid chromatography coupled to an electrochemical detector (ECD-HPLC). With this approach, a common effect on dopamine metabolism has been observed. These findings lead to a whole new academic project in which the effect of the different mechanisms that have been involved in the pathogenesis of PD is studied in order to understand the disease. If the common effect is confirmed in other cellular and animal models, these findings could lead to the involvement of pharmaceutical companies to develop a new therapy for the PD patients. 8 Table of Contents ABSTRACT ........................................................................................................................ 7 IMPACT STATEMENT…………………………...………………………………………8 TABLE OF CONTENTS ...................................................................................................... 9 LIST OF FIGURES ............................................................................................................. 15 LIST OF TABLES ............................................................................................................... 17 ABBREVIATIONS ............................................................................................................ 19 DECLARATION OF COLLABORATION ........................................................................... 25 ACKNOWLEDGMENTS ................................................................................................... 27 CHAPTER 1 INTRODUCTION .............................................................................................................. 29 1.1. DOPAMINE HOMEOSTASIS ......................................................................................31 1.1.1. Dopamine synthesis ................................................................................... 31 1.1.2. Dopamine neurotransmission ................................................................... 33 1.1.3. Dopamine recycling and degradation ....................................................... 35 1.1.4. Toxicity derived from dopamine metabolism .......................................... 37 1.1.5. Dopamine-related pathways ..................................................................... 40 1.2. ENZYMES AND COFACTORS OF THE DOPAMINE PATHWAY .......................................... 42 1.2.1. Tyrosine hydroxylase (TH) ........................................................................ 43 1.2.2. Aromatic L-amino acid decarboxylase (AADC) ......................................... 44 1.2.3. Catechol O-methyl transferase (COMT) .................................................... 44 1.2.4. Monoamine oxidase (MAO) ...................................................................... 45 1.2.5. Tetrahydrobiopterin (BH4) ....................................................................... 45 1.2.6. Pyridoxal phosphate (PLP) ....................................................................... 47 1.3. PARKINSON DISEASE............................................................................................. 47 1.3.1. PD and dopamine ...................................................................................... 48 1.3.2. PD and mitochondria ................................................................................ 50 1.3.3. PD and oxidative stress ............................................................................. 53 1.3.4. PD and lysosomes ...................................................................................... 57 1.3.5. PD, protein degradation and dysfunction in autophagy .......................... 58 1.3.6. Inherited mutations in PD ......................................................................... 60 1.4. AIMS .................................................................................................................. 63 9 CHAPTER 2 MATERIALS AND METHODS ......................................................................................... 65 2.1. MATERIALS ......................................................................................................... 67 2.2. TISSUE CULTURE: SH-SY5Y CELL LINE ................................................................... 68 2.2.1. Passaging and seeding .............................................................................. 68 2.2.2. Treatments ................................................................................................ 69 2.2.2.1. L-DOPA ............................................................................................................69 2.2.2.2. NSD-1015 ..........................................................................................................69 2.2.2.3. Rotenone ........................................................................................................ 70 2.2.2.4. CBE .................................................................... Error! Bookmark not defined. 2.2.3. Sample collection ....................................................................................... 71 2.2.3.1. Culture media: measurement of catecholamines release by HPLC .............. 71 2.2.3.3. Protein extraction: protein quantification, enzymatic activity and western blot 71 2.3. IMMUNOFLUORESCENCE ....................................................................................... 72 2.4. MAO ENZYMATIC ACTIVITY ASSAY ......................................................................... 73 2.4.1. Principle..................................................................................................... 73 2.4.2. Protocol ..................................................................................................... 74 2.4.3. Validation .................................................................................................
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