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Identifier

000461785

Title

Functional characterization of epithelial sodium channels/degenerins (ENaC/DEG) family members and determination of their role in organismal stress responses in C. elegans

Alternative Title

Λειτουργικός χαρακτηρισμός των γονιδίων μελών της οικογένειας των epithelial sodium channels /degenerins (ENaC/DEG) και προσδιορισμός του ρόλου τους στην απόκριση στο στρες στον οργανισμό C. elegans

Author

Πετράτου, Διονυσία

Thesis advisor

Ταβερναράκης, Νεκτάριος

Reviewer

Μαυροθαλασσίτης, Γεώργιος
Γραβάνης, Αχιλλέας
Καραγωγέος, Δόμνα
Αλεξανδράκη, Δέσποινα
Δελιδάκης, Χρήστος
Βαζοπούλου, Δάφνη

Abstract

Integration of sensory stimuli to appropriately modulate behavioral responses to environmental signals is critical for organismal survival. The nervous system initiates and modulates systemic stress responses ensuing physiological stress. Dopamine signaling is involved in several forms of behavioral plasticity. At the cellular level, ion homeostasis is of utmost importance for neuronal function, both for the maintenance of resting membrane potential and for the creation and propagation of action potentials. Imbalance in neuronal sodium homeostasis is associated with many nervous system pathologies. However, the effect of stress on neuronal sodium homeostasis, excitability, and survival is not explicit. In this study we focus on the ENaC/DEG family of sodium channels, specifically the Degenerins subfamily of Caenorhabditis elegans. Degenerins are expressed mainly in the nervous system and are implicated in several sensory modalities. Degenerins form transmembrane proteins that span twice the cytoplasmic membrane and assemble in homo-tetramers or hetero-tetramers to generate sodium channels. By implementing advanced imaging techniques, we found that DEL-2, DEL-3, and DEL-4 degenerins are expressed in dopaminergic, serotonergic, sensory, or motor neurons. We report that the ENaC/DEG family member DEL-4 assembles into a proton-inactivated, amiloride-sensitive, homomeric sodium channel. Distinct types of stress regulate this channel, which then triggers appropriate motor adaptations and organismal stress responses. DEL-4 operates at the neuronal cell membrane to modulate Caenorhabditis elegans locomotory behaviour. In Caenorhabtitis elegans the functionality of the dopamine pathway can be easily assessed by monitoring the locomotory response to environmental food availability cues, a behavior termed basal slowing. We showed that these ion channel proteins induce basal slowing response. They act through DOP-2 and DOP-3 dopamine receptors and affect the signaling at the neuromuscular junction. Limitation of DEL-4 reduces dopamine signaling and cholinergic neurotransmission at the neuromuscular junction. Concurrently, GABAergic signaling enhances at the neuromuscular junction. Heat stress and starvation reduce DEL-4 expression, which in turn adjusts the expression and activity of key stress response transcription factors, such as HSF-1, DAF-16, and SKN-1. Notably, comparable to heat stress and starvation, DEL-4 deficiency induces hyperpolarization of dopaminergic neurons to impact neurotransmission. DELs respond to gustatory stimuli and participate in proton and serotonin perception. Utilizing two humanized models of Parkinson's and Alzheimer's disease in C. elegans, we demonstrate that DEL-4 promotes neuronal survival in the context of these proteinopathies. DEL-4 deficiency enhances the degeneration of dopaminergic neurons in aged adults, upon control conditions, and in Parkinson’s and Alzheimer’s disease models. Our findings provide insight into the molecular mechanisms via which sodium channels uphold neuronal function and promote adaptation under stress.

Language

English

Subject

Metabolic stress

Neurotransmition

Δίαυλοι νατρίου

Νευροδιαβίβαση

Issue date

2024-04-17

Collection

School/Department--School of Medicine--Department of Medicine--Doctoral theses

Type of Work--Doctoral theses