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Identifier |
000453374 |
Title |
Investigating the role of the NEET protein family in ageing and neurodegeneration of the nematode Caenorhabditis elegans |
Alternative Title |
Μελέτη του ρόλου των πρωτεϊνών της οικογένειας NEET στη γήρανση και το νευροεκφυλισμό του νηματώδους Caenorhabditis elegans |
Author
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Πλουμή Χριστίνα
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Thesis advisor
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Ταβερναράκης, Νεκτάριος
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Reviewer
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Αλεξανδράκη, Δέσποινα
Δελιδάκης, Χρήστος
Βόντας, Ιωάννης
Καραγωγέως, Δόμνα
Χαμηλός, Γεώργιος
Παληκαράς, Κωνσταντίνος
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Abstract |
NEET family comprises a special type of Iron Sulfur Cluster (ISC) binding proteins implicated in various human pathologies ranging from neurodegeneration to cancer and reduced life expectancy. Despite the well-known structural and functional characteristics of mammalian NEETs, it remains largely enigmatic how their deficiency accelerates ageing and contributes to the manifestation of age-related pathologies. In our study we used the nematode Caenorhabditis elegans as a simple model organism to delineate the molecular pathways through which NEETs mediate their effects on longevity and healthspan. The nematode’s genome encodes for three NEET proteins: CISD-1, CISD-3.1 and CISD-3.2. CISD-1 is a single ortholog for both mammalian CISD1/mitoNEET and CISD2/Miner1, as it has one CDGSH domain for binding to ISCs. CISD-3.1 and CISD-3.2 have 2 CDGSH domains and thus are homologous to mammalian CISD3/MiNT. Our study is mainly focused on CISD-1, since its mammalian ortholog CISD2/Miner1 has been associated with Wolfram syndrome type 2, a rare neurodegenerative disorder characterized by premature ageing phenotypes. CISD-1 is a ubiquitously expressed protein localized at the outer mitochondrial membrane. CISD-1 deficient nematodes display reduced lifespan, enhanced neurodegeneration and exacerbated proteostasis. Our data reveal that CISD-1 preserves longevity through the mitochondrial intrinsic apoptosis pathway. Notably, the detrimental consequences of CISD-1 deficiency on lifespan, neuronal integrity and proteostasis are fully rescued upon depletion of the anti-apoptotic Bcl-2 nematode ortholog, CED-9. This rescue is dependent on autophagy induction, suggesting that CISD-1 mediates its effects by coupling the apoptosis and autophagic pathways through CED-9. In an attempt to further investigate the molecular function of CISD-1, we found that CISD-1 deficiency disturbs iron homeostasis, as evident by reduced Fe2+/Fetotal ratio in mitochondria, elevated ferritin expression and deregulated expression of iron-related genes. Importantly, our data suggest that intracellular iron abundance is critical for CISD-1 function, since mild iron supplementation is sufficient to decelerate ageing and partly ameliorates the disturbed proteostasis and neuronal integrity upon CISD-1 deficiency. Our work establishes CISD1 as a mitochondrial effector engaging autophagy and apoptosis pathways, and demonstrates novel approaches which could potentially facilitate the development of effective therapeutic interventions against WS2 or related diseases.
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Language |
English |
Subject |
Apoptosis |
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Autophagy |
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Iron |
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Mitochondria |
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Wolfram syndrome |
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Απόπτωση |
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Αυτοφαγία |
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Μιτοχόνδρια |
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Σίδηρος |
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Σύνδρομο Wolfram |
Issue date |
2023-04-05 |
Collection
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School/Department--School of Medicine--Department of Medicine--Doctoral theses
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Type of Work--Doctoral theses
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Permanent Link |
https://elocus.lib.uoc.gr//dlib/b/f/e/metadata-dlib-1675249187-155328-13819.tkl
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Views |
769 |
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