Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Author:
Petropoulou-Vathi Evangelia
Dissertation committee:
Στεφανής Λεωνίδας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παρασκευάς Γεώργιος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δοξάκης Επαμεινώντας, Ερευνητής Γ’, Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Μπουφίδου Φωτεινή, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Σταθόπουλος Πάνος-Αλέξης, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευαγγελοπούλου Μαρία-Ελευθερία, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Βασιλάτης Δημήτριος, Ερευνητής Γ’, Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Original Title:
Βιολογικοί δείκτες βασισμένοι στην πρωτεΐνη LRRK2 στη νόσο Πάρκινσον
Translated title:
Biomarkers based on LRRK2 protein in Parkinson's disease
Summary:
The central question of this PhD project was whether it is possible to reliably detect changes in the levels or activity of a protein called leucine rich repeat kinase 2 (LRRK2) in different biofluid samples from people affected by Parkinson’s disease (PD). There is considerable evidence now that LRRK2 activity plays a central role in the type of inflammatory response often seen in the different forms of familial and idiopathic PD (iPD), and for this reason participants of variant genetic backgrounds were studied here. It is known from experimental models that the most common LRRK2 mutation (G2019S) increases its kinase activity and this gain of function is considered toxic for cells; Consequently, affected and non-affected G2019S carriers were recruited and levels and activity of LRRK2 were compared to those of iPD patients as well as healthy controls (HC) in blood immune cells and urine biofluids. In addition, there is evidence indicating the importance of LRRK2 activity in mediating pathology related to α-synuclein, a central protein in PD pathogenesis, therefore; carriers of a mutation in the SNCA gene (A53T) that encodes α-synuclein, were also included. Mediated by both cell autonomous and non-cell autonomous mechanisms, the inhibition of LRRK2 kinase activity improves dopamine neuron survival, alters immune cell responses, and modulates pathological α-synuclein aggregation in response to overexpression or exposure to extracellular α-synuclein species. These lines of evidence suggest that it may be possible to detect changes in the activity of LRRK2 in samples from multiple forms of PD; and if this is the case, then it will be a powerful tool to be used as a biomarker in the staging of PD, as well as tracking its progression in patients who have already been diagnosed. Finally, such tests may be possible to discriminate between the different forms of PD and can also be utilised in clinical trials of new drugs being designed to inhibit the activity of LRRK2, to show that the drugs are having the desired effects on LRRK2. The focus of this study concerns several key proteins in the LRRK2 signalling pathway; including phosphorylation of LRRK2 itself as well as downstream substrates, such as the Rab GTPase family. While the field has made great advances in biomarker development for some targets important for PD, there is still a great need for assays measuring the activation of other signalling pathways. Our findings set the stage for further development of assays in the LRRK2 pathway and the establishment of sensitive signatures of LRRK2 activation in multiplexed immune-assays for better understanding of the disease.
Main subject category:
Health Sciences
Keywords:
Parkinson's disease, Biomarkers, LRRK2, Rab GTPases, a-synuclein
Number of references:
198
