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Identifier 000459738
Title The role of the deubiquitinase cyld in neuronal physiology amd ageing
Alternative Title Ο ρόλος της αποουβικιτινάσης Cyld στη νευρική φυσιολογία και γήρανση
Author Σωτηρίου, Αγγελική
Thesis advisor Ταβερναράκης, Νεκτάριος
Reviewer Νικολετοπούλου, Βασιλική
Καραγωγέως, Δόμνα
Χαμηλός, Γεώργιος
Χαραλαμπόπουλος, Ιωάννης
Παληκαράς, Κωσταντίνος
Βόντας, Ιωάννης
Abstract Ubiquitination is a critical regulator of cellular homeostasis, coordinating protein turnover and signal transduction. The concerted function of ubiquitinating and deubiquitinating enzymes dynamically shapes the proteomic landscape. Lysine63 polyubiquitination is highly abundant in the mammalian brain, fine-tuning synaptic scaffolding, efficacy and plasticity, thereby supporting fundamental neuronal functions. In the current PhD dissertation, we investigated the diverse functions of CYLD in neuronal physiology in the nematode Caenorhabditis elegans. CYLD is a lysine63-specific deubiquitinase recently implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer’s disease and frontotemporal dementia. We demonstrate that CYLD-1, the C. elegans CYLD homologue, is expressed in the nervous system and peripheral tissues and functions as a lysine63-specific DUB in vivo. During ageing, CYLD-1 protects against age-dependent motor neuron degeneration and promotes longevity and healthspan. In young nematodes, CYLD-1 plays a vital role in synaptic homeostasis, preserving synaptic number and neurotransmission through its catalytic DUB function. Depletion of CYLD from the nervous system results in behavioral deficits, impairing associative short-term memory. Mechanistically, our study reveals that CYLD-1 promotes autophagic flux in the nervous system and other tissues of the nematode. CYLD-1 deficiency leads to the accumulation of autolysosomes, which adopt an abnormal elongated morphology. In addition, we report perturbations of lysosomal morphology and acidification in cyld-1 mutant nematodes, indicative of lysosomal dysfunction. Our findings emphasize the pivotal role of lysine63 polyubiquitination as a master regulator of neuronal homeostasis and highlight CYLD and other deubiquitinating enzymes as potential therapeutic targets to alleviate age-related neurodegeneration and cognitive decline.
Language English
Subject Autophage
Neurodegeneration
Neurotransmission
Therapeutic agents
Αυτοφαγία
Νευροδιαβίβαση
Νευροεκφυλισμός
Issue date 2023-12-08
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/8/0/5/metadata-dlib-1698312672-241930-15596.tkl Bookmark and Share
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