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14 results on '"Goulielmaki, Evi"'

3. Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage.

Author

Arvanitaki, Ermioni S., Goulielmaki, Evi, Gkirtzimanaki, Katerina, Niotis, George, Tsakani, Edisona, Nenedaki, Electra, Rouska, Iliana, Kefalogianni, Mary, Xydias, Dionysios, Kalafatakis, Ilias, Psilodimitrakopoulos, Sotiris, Karagogeos, Domna, Schumacher, Björn, Stratakis, Emmanuel, and Garinis, George A.

Subjects
*EXTRACELLULAR vesicles, *DNA damage, *NEURODEGENERATION, *DNA repair, *CELL death
Abstract

DNA damage and neurodegenerative disorders are intimately linked but the underlying mechanism remains elusive. Here, we show that persistent DNA lesions in tissue-resident macrophages carrying an XPF-ERCC1 DNA repair defect trigger neuroinflammation and neuronal cell death in mice. We find that microglia accumulate dsDNAs and chromatin fragments in the cytosol, which are sensed thereby stimulating a viral-like immune response in Er1Cx/- and naturally aged murine brain. Cytosolic DNAs are packaged into extracellular vesicles (EVs) that are released from microglia and discharge their dsDNA cargo into IFN-responsive neurons triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, we developed targeting EVs to deliver recombinant DNase I to Er1Cx/- brain microglia in vivo. We show that EV-mediated elimination of cytosolic dsDNAs is sufficient to prevent neuroinflammation, reduce neuronal apoptosis, and delay the onset of neurodegenerative symptoms in Er1Cx/- mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age-related neurodegeneration. [ABSTRACT FROM AUTHOR]

Published
2024
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4. XPF interacts with TOP2B for R-loop processing and DNA looping on actively transcribed genes

Author

Chatzinikolaou, Georgia, primary, Stratigi, Kalliopi, additional, Siametis, Athanasios, additional, Goulielmaki, Evi, additional, Akalestou-Clocher, Alexia, additional, Tsamardinos, Ioannis, additional, Topalis, Pantelis, additional, Austin, Caroline, additional, Bouwman, Britta A. M., additional, Crosetto, Nicola, additional, Altmüller, Janine, additional, and Garinis, George A., additional

Published
2023
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7. R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage

Author

Chatzidoukaki, Ourania, Stratigi, Kalliopi, Goulielmaki, Evi, Niotis, George, Akalestou-Clocher, Alexia, Gkirtzimanaki, Katerina, Zafeiropoulos, Alexandros, Altmueller, Janine, Topalis, Pantelis, Garinis, George A., Chatzidoukaki, Ourania, Stratigi, Kalliopi, Goulielmaki, Evi, Niotis, George, Akalestou-Clocher, Alexia, Gkirtzimanaki, Katerina, Zafeiropoulos, Alexandros, Altmueller, Janine, Topalis, Pantelis, and Garinis, George A.

Abstract

How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue architecture, and chronic pancreatitis in mice with an inborn defect in the excision repair cross complementation group 1 (Ercc1) gene. We find that DNA damage-driven R-loops causally contribute to the active release and buildup of single-stranded DNAs (ssDNAs) in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or ribonuclease H nucleases in inflamed Ercc1(-/-) pancreatic cells. Treatment of Ercc1(-/-) animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration, Ercc1(-/-) paving the way for novel rationalized intervention strategies against age-related chronic inflammation.

Published
2021

8. Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage

Author

Goulielmaki, Evi Ioannidou, Anna Tsekrekou, Maria Stratigi, Kalliopi Poutakidou, Ioanna K. Gkirtzimanaki, Katerina and Aivaliotis, Michalis Evangelou, Konstantinos Topalis, Pantelis and Altmueller, Janine Gorgoulis, Vassilis G. Chatzinikolaou, Georgia Garinis, George A.

Abstract

DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1(F/-)) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1(F/-) animal sera and are secreted in macrophage media after DNA damage. The Er1(F/-) EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.

Published
2020

9. DNA Damage Response and Metabolic Reprogramming in Health and Disease

Author

Chatzidoukaki, Ourania, Goulielmaki, Evi, Schumacher, Bjoern, Garinis, George A., Chatzidoukaki, Ourania, Goulielmaki, Evi, Schumacher, Bjoern, and Garinis, George A.

Abstract

Nuclear DNA damage contributes to cellular malfunction and the premature onset of age-related diseases, including cancer. Until recently, the canonical DNA damage response (DDR) was thought to represent a collection of nuclear processes that detect, signal and repair damaged DNA. However, recent evidence suggests that beyond nuclear events, the DDR rewires an intricate network of metabolic circuits, fine-tunes protein synthesis, trafficking, and secretion as well as balances growth with defense strategies in response to genotoxic insults. In this review, we discuss how the active DDR signaling mobilizes extranuclear and systemic responses to promote cellular homeostasis and organismal survival in health and disease.

Published
2020

10. Targeted Deletion of a Plasmodium Site-2 Protease Impairs Life Cycle Progression in the Mammalian Host

Author

Koussis, Konstantinos, Goulielmaki, Evi, Chalari, Anna, Withers-Martinez, Chrislaine, Siden-Kiamos, Inga, Matuschewski, Kai, and Loukeris, Thanasis G.

Subjects
Plasmodium, Life Cycles, Erythrocytes, Arthropoda, Physiology, Epidemiology, Parasitic Life Cycles, lcsh:Medicine, Disease Vectors, Biochemistry, Mosquitoes, Mice, Parasite Groups, Medicine and Health Sciences, Parasitic Diseases, Animals, Amino Acid Sequence, lcsh:Science, Protozoans, Cell Nucleus, Sequence Homology, Amino Acid, lcsh:R, Organisms, Malarial Parasites, Biology and Life Sciences, Proteins, Proteases, Hematology, Invertebrates, Parasitic Protozoans, Enzymes, Body Fluids, Insect Vectors, Malaria, Insects, Mice, Inbred C57BL, Disease Models, Animal, Blood, Liver, Sporozoites, Enzymology, lcsh:Q, Parasitology, Anatomy, Apicomplexa, Research Article, Developmental Biology, Peptide Hydrolases
Abstract

Site-2 proteases (S2P) belong to the M50 family of metalloproteases, which typically perform essential roles by mediating activation of membrane-bound transcription factors through regulated intramembrane proteolysis (RIP). Protease-dependent liberation of dormant transcription factors triggers diverse cellular responses, such as sterol regulation, Notch signalling and the unfolded protein response. Plasmodium parasites rely on regulated proteolysis for controlling essential pathways throughout the life cycle. In this study we examine the Plasmodium-encoded S2P in a murine malaria model and show that it is expressed in all stages of Plasmodium development. Localisation studies by endogenous gene tagging revealed that in all invasive stages the protein is in close proximity to the nucleus. Ablation of PbS2P by reverse genetics leads to reduced growth rates during liver and blood infection and, hence, virulence attenuation. Strikingly, absence of PbS2P was compatible with parasite life cycle progression in the mosquito and mammalian hosts under physiological conditions, suggesting redundant or dispensable roles in vivo.

Published
2017

14. Functional Characterization of AnophelesMatrix Metalloprotease 1 Reveals Its Agonistic Role during Sporogonic Development of Malaria Parasites

Author

Goulielmaki, Evi, Sidén-Kiamos, I., and Loukeris, Thanasis G.

Abstract

ABSTRACTThe ability to invade tissues is a unique characteristic of the malaria stages that develop/differentiate within the mosquitoes (ookinetes and sporozoites). On the other hand, tissue invasion by many pathogens has often been associated with increased matrix metalloprotease (MMP) activity in the invaded tissues. By employing cell biology and reverse genetics, we studied the expression and explored putative functions of one of the three MMPs encoded in the genome of the malaria vector Anopheles gambiae, namely, the Anopheles gambiaeMMP1(AgMMP1) gene, during the processes of blood digestion, midgut epithelium invasion by Plasmodiumookinetes, and oocyst development. We show that AgMMP1 exists in two alternative isoforms resulting from alternative splicing; one secreted (S-MMP1) and associated with hemocytes, and one membrane type (MT-MMP1) enriched in the cell attachment sites of the midgut epithelium. MT-MMP1 showed a remarkable response to ookinete midgut invasion manifested by increased expression, enhanced zymogen maturation, and subcellular redistribution, all indicative of an implication in the midgut epithelial healing that accompanies ookinete invasion. Importantly, RNA interference (RNAi)-mediated silencing of the AgMMP1gene revealed a postinvasion protective function of AgMMP1 during oocyst development. The combined results link for the first time an MMP with vector competence and mosquito-Plasmodiuminteractions.

Published
2014
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