Biomarkers in Parkinson's Disease

Doctoral Dissertation uoadl:2885095 355 Read counter

Unit:
Faculty of Medicine
Library of the School of Health Sciences
Deposit date:
2019-11-08
Year:
2019
Author:
Papagiannakis Nikolaos
Dissertation committee:
Στεφανής Λεωνίδας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Καπάκη Ελισσάβετ, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Βεκρέλλης Κωνσταντίνος, Ερευνητής Β, Ίδρυμα Ιατροβιολογικών Ερευνών της Ακαδημίας Αθηνών
Παρασκευάς Γεώργιος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παπαγεωργίου Σωκράτης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κούτσης Γεώργιος, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δοξάκης Επαμεινώντας, Ερευνητής Γ, Ίδρυμα Ιατροβιολογικών Ερευνών της Ακαδημίας Αθηνών
Original Title:
Βιολογικοί δείκτες στη νόσο του Πάρκινσον
Languages:
Greek
Translated title:
Biomarkers in Parkinson's Disease
Summary:
BACKGROUND: Reduced expression of lysosomal-associated membrane protein 2a and heatshock-cognate 70 proteins, involved in chaperone-mediated autophagy and of glucocerebrosidase, is reported in PD brains. The aim of this study was to identify systemic alterations in lysosomal-associated membrane protein 2a, heatshock cognate-70, and glucocerebrosidase levels/activity in peripheral blood mononuclear cells from PD patients.
Alpha-synuclein aggregation is considered one of the main causes of Parkinson's Disease (PD). Malfunction of autophagy-lysosomal pathways is believed to be an underlying mechanism of α-synuclein aggregation. Although such malfunction has been observed in PD brains, it is unclear whether it may also occur in extraneuronal tissues.
Variations of α-synuclein levels or species have been reported in Parkinson's Disease (PD). There has been little systematic examination of erythrocytes, a rich source of α-synuclein.
METHODS: Protein/mRNA levels were assessed in PD patients from genetically undetermined background, alpha-synuclein (G209A/A53T), or glucocerebrosidase mutation carriers and age-/sex-matched controls.
Total protein degradation in cultured PBMCs was measured by labelling the cells with 3H-leucine using pulse-chase experiments. Different inhibitors were used to measure a range of autophagic pathways.
Erythrocyte membranes were obtained from PD patients (mutation carriers in the α-synuclein gene (A53T-PD) and glucocerebrosidase gene (GBA-PD) (n=18 each), and patients without known mutations (GU-PD, n=56)), and age-/sex-matched controls (n=56). Levels of monomeric and dimeric α-synuclein were assessed using Western immunoblotting.
RESULTS: Heatshock cognate 70 protein levels were reduced in all PD groups, whereas its mRNA levels were decreased only in the genetically undetermined group. Glucocerebrosidase protein levels were decreased only in the genetic PD groups, whereas increased mRNA levels and decreased activity were detected only in the glucocerebrosidase mutation group.
Protein degradation through the main autophagic pathways is reduced in PD patients (n = 18) compared to age- and sex-matched healthy controls (n = 18), (macroautophagy, p = .018; Chaperone-Mediated autophagy, p = .04; and total lysosomal function, p = .007).
A statistically significant increase of α-synuclein dimer and dimer to monomer ratio was found in GBA-PD and GU-PD. In contrast, dimer levels of A53T-PD were not different from controls. No difference was found in α-synuclein monomer levels.
CONCLUSIONS: Reduced heatshock cognate-70 levels are suggestive of an apparent systemic chaperone-mediated autophagy dysfunction irrespective of genetic background. Glucocerebrosidase activity may serve as a screening tool to identify glucocerebrosidase mutation carriers with PD.
Lysosomal dysfunction is present in cultured PBMCs of PD patients, suggesting that it may reflect a systemic feature of the disease.
The increased α-synuclein dimer in GBA-PD and GU-PD is suggestive of an apparent systemic dysfunction causing the dimerization, and potentially oligomerization, of α-synuclein. These results may have implications for PD pathogenesis and biomarker development.
Main subject category:
Health Sciences
Keywords:
Parkinson's Disease, α-synuclein, Lysosomes, Autophagy
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
357
Number of pages:
176
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