Κατεύθυνση Κλινική Βιοχημεία - Μοριακή Διαγνωστική
Library of the School of Science

2024-04-22

2024

Tsangaridou Stefani

Διδώ Βασιλακοπούλου, Αναπληρώτρια Καθηγήτρια, Tμήμα Βιολογίας, EΚΠΑ, (Επιβλέπουσα)
Διαμαντής Σιδέρης Καθηγητής Τμήμα Βιολογίας ΕΚΠΑ,
Νίκη Βασιλάκη Ερευνήτρια Β’, Ελληνικό Ινστιτούτο Παστέρ

Συσχέτηση της L-Dopa αποκαρβοξυλάσης με τον νευροεκφυλισμό

Greek

Association of L-Dopa decarboxylase with neurodegeneration

Neurodegenerative diseases are a complex branch of neurological diseases whose pathophysiology remains unclear. Alzheimer's disease (AD) is one of the most common neurodegenerative disorders associated with age or inherited mutations. The progression of AD is associated with accumulation of cytotoxic β-amyloid (Aβ) peptide and hyperphosphorylated tau protein in combination with other pathological features such as loss of synaptic function, defective energy metabolism, imbalances in protein and mineral homeostasis. Amyloid precursor protein (APP) is a membrane protein thought to play a major role in the pathology of the disease. It is known that APP under normal conditions follows a non-amyloidogenic pathway; however, it can proceed in an amyloidogenic pathway, which leads to the formation of extracellular deleterious Aβ plaques. The second most common neurodegenerative disorder is Parkinson's disease. A-synuclein is a presynaptic neuronal protein that is genetically and neuropathologically linked to Parkinson's disease (PD). Its abnormal soluble oligomeric conformations, so-called protofibrils, are believed to be the toxic species that mediate cellular homeostasis disruption and neuronal death through effects on various intracellular targets, including synaptic function. In addition, secreted α-synuclein may exert deleterious effects on neighbouring cells, thereby potentially contributing to disease dissemination. This protein is abundant in dopamine-producing nerve cells and is particularly concentrated in the brain. The emergence of DDC as a potential biomarker of Parkinsonian disorders brings to the fore the necessity of further study of the emerging complex role of the enzyme. It is well known that DDC is the enzyme for the conversion of L-DOPA to dopamine in the catecholamine biosynthesis pathway. In the present thesis, an attempt was made to determine the effect of the DDC enzyme on the proteolytic processing of the amyloid precursor protein (APP) and on the expression and aggregation levels of oligomeric forms of endogenous α-synuclein as a function of oxidative (H2O2) and antioxidant (l-ascorbic acid) conditions. The cell system used is a simulated model of dopaminergic neurons. The CHO-K1 cell line was chosen which is devoid of the enzymes and proteins associated with the production and metabolism of catecholamines found in all neuronal cells. To conduct the experiments, the above cell system was co-infected with human DDC cDNA. The set of results presented in this thesis confirms the involvement of the DDC enzyme in neurodegeneration in both Alzheimer's and Parkinson's disease, supporting the view that neurodegenerative diseases have a common molecular basis. Based on the results, we demonstrate the resistance induced by the DDC enzyme to cell death under oxidative stress and, by extension, the possible involvement of the enzyme in the mechanism of oxidative stress. Our observations confirm the dual role of ascorbic acid while highlighting a possible barrier resulting from the action of ascorbic acid towards the role of DDC. In addition, our observations suggest that DDC may be involved in the proteolytic process but also guides the proteolysis of APP towards the amyloidogenic pathway. Finally, cells that were infected with human DDC cDNA showed a tendency towards induction of α-synuclein aggregation.Thus, further study of the complex role of DDC seems necessary.

Science

DDC , APP , a-synuclein, neurodegeneration, l-ascorbic acid , H2O2

No

117

Yes

313

117

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https://pergamos.lib.uoa.gr/uoa/dl/object/3396810