Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Author:
Nakos-Bimpos Modestos
Dissertation committee:
Γεώργιος Χρούσος , Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Λεωνίδας Στεφανής, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Χριστίνα Δάλλα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αικατερίνη Αντωνίου, Καθηγήτρια, Τμήμα Ιατρικής, Πανεπιστήμιο Ιωαννίνων
Hilal Lashuel, Associate Professor, School of Life Sciences, EPFL
Στυλιανή Βλάχου, Associate Professor, School of Psychology, Dublin City University
Κωνσταντίνος Παληκαράς, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Διερεύνηση της επίδρασης του στρες στις νευροεκφυλιστικές διεργασίες επαγόμενες από την πρωτεΐνη α-συνουκλεΐνη
Translated title:
Investigation of the effect of stress on neurodegenerative processes induced by the protein alpha-synuclein
Summary:
An emerging connection between chronic stress and the pathogenesis of Parkinson’s disease (PD) is gaining increased attention. Despite the plethora of evidence linking the presynaptic neuronal protein alpha-synuclein (asyn) to PD pathogenesis, it remains unclear whether stress system dysfunction is present in PD, if asyn is involved, and if both together promote neurodegeneration. To explore these questions, we evaluated stress axis function in transgenic rats overexpressing full-length human asyn (asyn BAC rats) and performed multi-level stress and PD phenotyping following two different paradigms of chronic stress exposure. While the transgenic rats overexpressing human wildtype asyn are characterized by hypothalamic-pituitary-adrenal (HPA) axis dysregulation, chronic unpredictable stress and corticosterone exposure further intensify nigrostriatal degeneration, increased serine129 phosphorylated asyn (pS129), and neuroinflammation, ultimately leading to phenoconversion from a prodromal to an overt motor PD phenotype. Notably, chronic corticosterone in asyn BAC rats leads to a robust, twofold increase in pS129 levels in the hypothalamus, the master regulator of the stress response, while the hippocampus, both a regulator and target of stress, also shows elevated pS129 asyn and altered stress signaling. In BAC rats, chronic stress and human asyn disrupt genes and cellular pathways linked to neuronal development, synaptic function, and neurotransmitter signaling in the hippocampus, indicating impaired brain connectivity and synaptic function—archetypal features of neurodegenerative diseases. Chronic stress further amplifies these disruptions, leading to compensatory upregulation of mitochondrial and detoxification pathways, highlighting increased cellular stress suggesting that the combination of stress and asyn pathology accelerates synaptic dysfunction and the progression of PD. Additionally, asyn overexpression in BAC rats reproduces a microbiota profile of genera and metabolites similar to those observed in PD patients, with both stress paradigms leading to the upregulation of the same microbiota populations in BAC and WT rats. Stress interaction with the BAC genotype, reveals significant changes in Subdoligranulum and Peptococcus populations. While the impact of enteric system changes and microbiome shifts is complex, these findings provide an opportunity to identify and evaluate specific bacterial species for their potential protective or harmful effects on restoring normal gut function and eubiosis, and indirectly, on neurodegeneration. Taken together, our findings link stress to asyn through microbiota-gut-brain axis dysregulation and provide evidence that elevated circulating glucocorticoids can contribute to asyn-induced neurodegeneration, ultimately triggering phenoconversion from prodromal to overt PD.
Main subject category:
Health Sciences
Keywords:
Parkinson’s disease, Alpha-synuclein, Chronic stress, Corticosterone, HPA axis, Gut microbiome
Number of references:
535
