Academic literature on the topic 'CHCHD4'
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Journal articles on the topic "CHCHD4"
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Al-Habib, Hasan, and Margaret Ashcroft. "CHCHD4 (MIA40) and the mitochondrial disulfide relay system." Biochemical Society Transactions 49, no. 1 (February 18, 2021): 17–27. http://dx.doi.org/10.1042/bst20190232.
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Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the regulation of bioenergetic and biosynthetic pathways, as well as regulating cellular signalling and transcriptional networks. In this way, mitochondria are central to the cell's homeostatic machinery, and as such mitochondrial dysfunction underlies the pathology of a diverse range of diseases including mitochondrial disease and cancer. Mitochondrial import pathways and targeting mechanisms provide the means to transport into mitochondria the hundreds of nuclear-encoded mitochondrial proteins that are critical for the organelle's many functions. One such import pathway is the highly evolutionarily conserved disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS), whereby proteins undergo a form of oxidation-dependent protein import. A central component of the DRS is the oxidoreductase coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein 4 (CHCHD4, also known as MIA40), the human homologue of yeast Mia40. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating the cellular response to low oxygen (hypoxia) and metabolism in cancer.
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Imai, Yuzuru, Hongrui Meng, Kahori Shiba-Fukushima, and Nobutaka Hattori. "Twin CHCH Proteins, CHCHD2, and CHCHD10: Key Molecules of Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia." International Journal of Molecular Sciences 20, no. 4 (February 20, 2019): 908. http://dx.doi.org/10.3390/ijms20040908.
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Mutations of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) have been found to be linked to Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and/or frontotemporal lobe dementia (FTD). CHCHD2 and CHCHD10 proteins, which are homologous proteins with 54% identity in amino acid sequence, belong to the mitochondrial coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family. A series of studies reveals that these twin proteins form a multimodal complex, producing a variety of pathophysiology by the disease-causing variants of these proteins. In this review, we summarize the present knowledge about the physiological and pathological roles of twin proteins, CHCHD2 and CHCHD10, in neurodegenerative diseases.
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Zhou, Wei, Dongrui Ma, and Eng-King Tan. "Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications." Neuroscientist 26, no. 2 (September 16, 2019): 170–84. http://dx.doi.org/10.1177/1073858419871214.
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CHCHD2 mutations have been identified in various neurological diseases such as Parkinson’s disease (PD), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). It is also the first mitochondrial gene whose mutations lead to PD. CHCHD10 is a homolog of CHCHD2; similar to CHCHD2, various mutations of CHCHD10 have been identified in a broad spectrum of neurological disorders, including FTD and AD, with a high frequency of CHCHD10 mutations found in motor neuron diseases. Functionally, CHCHD2 and CHCHD10 have been demonstrated to interact with each other in mitochondria. Recent studies link the biological functions of CHCHD2 to the MICOS complex (mitochondrial inner membrane organizing system). Multiple experimental models suggest that CHCHD2 maintains mitochondrial cristae and disease-associated CHCHD2 mutations function in a loss-of-function manner. However, both CHCHD2 and CHCHD10 knockout mouse models appear phenotypically normal, with no obvious mitochondrial defects. Strategies to maintain or enhance mitochondria cristae could provide opportunities to correct the associated cellular defects in disease state and unravel potential novel targets for CHCHD2-linked neurological conditions.
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Hangen, Emilie, Olivier Féraud, Sylvie Lachkar, Haiwei Mou, Nunzianna Doti, Gian Maria Fimia, Ngoc-vy Lam, et al. "Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis." Molecular Cell 58, no. 6 (June 2015): 1001–14. http://dx.doi.org/10.1016/j.molcel.2015.04.020.
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Reinhardt, Camille, Giuseppe Arena, Kenza Nedara, Ruairidh Edwards, Catherine Brenner, Kostas Tokatlidis, and Nazanine Modjtahedi. "AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1866, no. 6 (June 2020): 165746. http://dx.doi.org/10.1016/j.bbadis.2020.165746.
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Modjtahedi, Nazanine, and Guido Kroemer. "CHCHD4 links AIF to the biogenesis of respiratory chain complex I." Molecular & Cellular Oncology 3, no. 2 (July 29, 2015): e1074332. http://dx.doi.org/10.1080/23723556.2015.1074332.
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Gomez, Adriana Morales, Nathan Staff, and Stephen C. Ekker. "320 Genetic Compensation as a mechanism underlying patients with Rare ALS." Journal of Clinical and Translational Science 6, s1 (April 2022): 57. http://dx.doi.org/10.1017/cts.2022.178.
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OBJECTIVES/GOALS: Rare mutations in CHCHD10 gene are found in 1% of patients with familial Amyotrophic lateral sclerosis (ALS). The overall goal of this study is to utilize induced pluripotent stem cells (iPSCs) as an in vitro model organism for rare ALS variants to evaluate the mechanism of transcription adaptation of CHCHD10/2 as a potential therapeutic. METHODS/STUDY POPULATION: Point mutations on normal iPSCs was performed via Donorguide CRISPR/Cas9. The single stranded RNA/DNA donors contain genetic alterations of CHCHD10: Pro12Ser, Arg15Leu, Pro23Leu, Pro34Ser, Ser59Leu, Gly66Val, Pro80Leu, Tyr92Cys and Gln102His. Ribonucleoprotein electroporation was used to transfect iPSCs and DNA sequencing was used to validate gene editing. To validate transcriptional adaption, changes in levels of protein and gene expression were measured via immunoblot and quantification of CHCHD10 and CHCHCD2 was performed from whole cells lysates of the edited iPSCs. RESULTS/ANTICIPATED RESULTS: We anticipate that CHCHD2 transcriptional adaptation can functionally compensate for the locus loss of function of CHCHD10. This mechanism of transcriptional adaptation may contribute to an explanation for variation in clinical manifestations of patient phenotypes. DISCUSSION/SIGNIFICANCE: This study supplies further evidence for genetic modification as a treatment option for diseases with point mutation causal or enabling mechanisms, including some variants of ALS. Future work will explore the gene-correction from an ALS patient with a known CHCHD10-R15L variant.
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Zavileyskiy, Lev, and Victoria Bunik. "Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes." Biomolecules 12, no. 2 (February 18, 2022): 327. http://dx.doi.org/10.3390/biom12020327.
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A transcription factor p53 is activated upon cellular exposure to endogenous and exogenous stresses, triggering either homeostatic correction or cell death. Depending on the stress level, often measurable as DNA damage, the dual outcome is supported by p53 binding to a number of regulatory and metabolic proteins. Apart from the nucleus, p53 localizes to mitochondria, endoplasmic reticulum and cytosol. We consider non-nuclear heterologous protein complexes of p53, their structural determinants, regulatory post-translational modifications and the role in intricate p53 functions. The p53 heterologous complexes regulate the folding, trafficking and/or action of interacting partners in cellular compartments. Some of them mainly sequester p53 (HSP proteins, G6PD, LONP1) or its partners (RRM2B, PRKN) in specific locations. Formation of other complexes (with ATP2A2, ATP5PO, BAX, BCL2L1, CHCHD4, PPIF, POLG, SOD2, SSBP1, TFAM) depends on p53 upregulation according to the stress level. The p53 complexes with SIRT2, MUL1, USP7, TXN, PIN1 and PPIF control regulation of p53 function through post-translational modifications, such as lysine acetylation or ubiquitination, cysteine/cystine redox transformation and peptidyl-prolyl cis-trans isomerization. Redox sensitivity of p53 functions is supported by (i) thioredoxin-dependent reduction of p53 disulfides, (ii) inhibition of the thioredoxin-dependent deoxyribonucleotide synthesis by p53 binding to RRM2B and (iii) changed intracellular distribution of p53 through its oxidation by CHCHD4 in the mitochondrial intermembrane space. Increasing knowledge on the structure, function and (patho)physiological significance of the p53 heterologous complexes will enable a fine tuning of the settings-dependent p53 programs, using small molecule regulators of specific protein–protein interactions of p53.
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Modjtahedi, Nazanine, Emilie Hangen, Patrick Gonin, and Guido Kroemer. "Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor CHCHD4." Cell Cycle 14, no. 17 (July 29, 2015): 2743–47. http://dx.doi.org/10.1080/15384101.2015.1068477.
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Erdogan, Alican J., Muna Ali, Markus Habich, Silja L. Salscheider, Laura Schu, Carmelina Petrungaro, Luke W. Thomas, et al. "The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo." Redox Biology 17 (July 2018): 200–206. http://dx.doi.org/10.1016/j.redox.2018.03.014.
Full textDissertations / Theses on the topic "CHCHD4"
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COCOMAZZI, PAOLO GIUSEPPE. "THE DOUBLE LIFE OF THE APOPTOSIS INDUCING FACTOR (AIF): THE PRO-VITAL ROLE OF A PRO-DEATH PROTEIN." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/712701.
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Beside its apoptotic function, the Apoptosis Inducing Factor (AIF), a highly conserved mitochondrial flavoprotein, plays a pro-vital role in eukaryotic cells through its interaction with CHCHD4, a mitochondrial protein that contributes to oxidative folding of respiratory complexes’ subunits. A unique feature of AIF is the ability to form a tight, air-stable charge-transfer complex (CT complex) upon reaction with NAD(H), which leads to protein dimerization modulating the affinity for its ligands.
To date, nine point mutations of the human AIF gene were found to cause rare and severe neurodegenerative mitochondriopathies. To define the molecular bases of the pathogenicity of AIF variants, we selected a set of AIF mutations (G337E, D236G, G261S and F133L) and investigated their effects on both AIF molecular properties and its interaction with CHCHD4. To this aim, a combination of biophysical techniques, Microscale Thermophoresis (MST) and structural biology was used. AIF variants CT complex stability was evaluated studying its reoxidation by O2. Interestingly, CT complex of G337E and G261S forms displayed a faster oxidation compared to wild type AIF, indicating a lower stability. Moreover, the 3D structures of the CT complex of AIF-D236G and of AIF-F133L both in oxidized and CT complex state were obtained, showing, however, no significant structural rearrangements with respect to the wild type protein. Hence, we investigated possible alterations of the interaction with CHCHD4 induced by AIF pathogenic mutations. Through a MST approach, for the first time we quantitatively studied redox-dependent effects of AIF amino acid replacements on its affinity for CHCHD4, revealing a possible involvement of the G337 residue in protein-protein complex formation. We characterized the AIF-CHCHD4 complex also from a structural point of view using the Small-Angle X-ray Scattering (SAXS) technique, through which we identified a putative interaction region between the two proteins. In addition, all SAXS models obtained revealed that the solvent-exposed G337 residue is localized in the neighborhood of the identified region, in agreement with a possible role of this residue in complex formation. Our results, not only shed new light on AIF-CHCHD4 relationship, but also provide a possible explanation of the pathogenicity of the AIF G337E allelic variant.
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Nedara, Kenza. "Impact de l'expression de TRIAP1, substrat de la voie d'import AIF/CHCHD4, sur la prolifération des cellules cancéreuses et leur réponse au stress métabolique." Thesis, université Paris-Saclay, 2022. http://www.theses.fr/2022UPASL032.
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Dans les conditions physiologiques, les mitochondries jouent un rôle fondamental dans la survie, la différentiation et l'état d'activation des cellules, en participant au métabolisme bioénergétique mais aussi à la synthèse des macromolécules, la régulation des voies de signalisation ou le contrôle de l'épigénome. Cet organite est bifonctionnel car son implication est également établie dans la réponse cellulaire au stress ou à des signaux apoptotiques. L'activité mitochondriale est étroitement liée à sa morphologie, qui est contrôlée par un ensemble de protéines impliquées dans le remodelage de son ultrastructure et de sa dynamique fusion/fission. Ces protéines sont cruciales pour l'adaptation de l'activité mitochondriale aux besoins bioénergétique de la cellule. Elles sont également des acteurs clés dans la régulation des processus cellulaires et des voies de signalisation qui nécessitent l'interaction des mitochondries avec d'autres compartiments cellulaires tels que le réticulum endoplasmique.Récemment, une nouvelle classe de protéines façonnant les mitochondries (TRIAP1, CHCHD2, CHCHD3, CHCHD6 et CHCHD10) a été décrite. Ces protéines contiennent un domaine coiled-coil-helix (CHCHD) et sont importées dans l'espace intermembranaire de l'organite grâce à l'activité de la machinerie d'import redox-dépendante Mia40/CHCHD4. Elles représentent des cibles thérapeutiques potentielles car leur expression anormale ou leur activité déficiente est associée à divers types de pathologies humaines telle que les maladies neurodégénératives et le cancer. Au cours de ma thèse je me suis particulièrement intéressée à la protéine TRIAP1 qui est surexprimée dans de nombreux types de cancers. Les expériences d'ARN interférence ou de surexpression de la protéine recombinante, dans un modèle de cancer colorectal, ont montré que l'expression de TRIAP1 favorise la prolifération des cellules et la croissance tumorale. Nos résultats montrent que la déplétion de TRIAP1, altère l'ultrastructure mitochondriale, impacte le profil métabolomique et lipidomique des cellules et engendre une signalisation rétrograde vers le noyau qui modifie le programme d'expression génique. Par ailleurs, nos résultats montrent que la perte de TRIAP1 modifie la réponse des cellules cancéreuses à des conditions de stress métabolique. Dans l'ensemble, nos résultats soulignent l'importance de la protéine TRIAP1 dans la plasticité métabolique des cellules cancéreuses. Une meilleure compréhension des bases moléculaires de l'activité mitochondriale de TRIAP1 dans les cellules cancéreuses permettrait de mieux appréhender l'avantage sélectif qu'apporte sa surexpression aux cellules tumoralesUnder physiological conditions, mitochondria play a fundamental role in cell survival, differentiation and activation by participating in bioenergetic metabolism, synthesis of macromolecules, regulation of signaling pathways or control of the epigenome. This organelle is bifunctional as its involvement is also well established in the cellular response to stress or apoptotic signals. The regulation of the mitochondrial activity is closely linked to its morphology, which is controlled by a set of proteins involved in the remodeling of its ultrastructure and fusion/fission dynamics. These proteins are crucial for the adaptation of mitochondrial biogenesis and activity to the bioenergetic needs of the cell. They are also key players in the regulation of cellular processes and signaling pathways that require the interaction of mitochondria with other cellular compartments such as the endoplasmic reticulum.Recently, a new class of mitochondria shaping proteins (TRIAP1, CHCHD2, CHCHD3, CHCHD6 and CHCHD10) was described. These proteins contain a coiled-coil-helix (CHCHD) domain and are imported into the intermembrane space of the organelle through the activity of the redox-dependent Mia40/CHCHD4 import machinery. They represent potential therapeutic targets as their abnormal expression or deficient activity has been associated with various human pathologies such as neurodegenerative diseases and cancer. During my thesis I studied the TRIAP1 protein which is overexpressed in many types of cancers. RNA interference or recombinant protein overexpression experiments , in a colorectal cancer model, showed that TRIAP1 expression promotes cell proliferation and tumor growth. Our results show that TRIAP1 depletion alters mitochondrial ultrastructure, impacts the metabolomic and lipidomic profile of the cells and induces a retrograde signaling to the nucleus that modifies the gene expression program. Furthermore, our results show that loss of TRIAP1 alters the response of cancer cells to metabolic stress conditions. Overall, our results highlight the relevance of TRIAP1 in the metabolic plasticity of cancer cells. A better understanding of the molecular basis of the mitochondrial activity of TRIAP1 in cancer cells should provide a better understanding of the selective advantage that its overexpression provides to tumor cells
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Reinhardt, Camille. "Impact de la voie d’import mitochondrial contrôlée par le complexe AIF/CHCHD4 sur la survie des cellules cancéreuses et la réponse aux traitements anticancéreux." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS542.
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Dans la majorité des cas, les mitochondries sont nécessaires à la tumorigenèse et à la réponse des cellules cancéreuses aux signaux générés par les facteurs micro-environnementaux (exemples : privation de nutriments, hypoxie) ou par les traitements anticancéreux (exemples : chimiothérapie, radiothérapie). Presque toutes les protéines mitochondriales sont codées par le génome nucléaire et importées dans l'organelle. Des machineries d'import ont donc évolué afin de répondre aux besoins d'import protéique. Dans ce contexte, la machinerie régulée par CHCHD4/Mia40 fonctionne dans l’espace intermembranaire et contrôle l’import d’un groupe de protéines (substrats) qui joue des rôles importants dans la survie et la réponse au stress. Les substrats de CHCHD4/Mia40 sont impliqués dans un vaste panel d’activités mitochondriales qui inclut la biogenèse des complexes de la chaîne respiratoire, l’homéostasie lipidique, le stockage du calcium, ainsi que l'ultrastructure et la dynamique mitochondriale. Ce programme de thèse a été dédié à l’étude de la voie d’import CHCHD4/Mia40 dans les cellules cancéreuses et a porté un intérêt tout particulier à l'un des substrats CHCHD4/Mia40 qui façonne l'ultrastructure mitochondriale. En utilisant des techniques d’ARN interférence et de sur-expression de protéines recombinantes, dans un modèle de cancer du côlon, nous avons montré que l’expression du substrat étudié a un effet crucial sur la prolifération et la croissance tumorale. Nos données ont également impliqué cette protéine dans la réponse aux traitements anticancéreux. Dans l'ensemble, ces travaux ouvrent un nouveau champ d'investigations qui non seulement permettra de mieux comprendre la plasticité métabolique des cellules cancéreuses, mais aidera également à identifier de nouveaux biomarqueurs métaboliquesIn the vast majority of cases, mitochondria are required for tumorigenesis and also for the tumoral response to signals generated by the microenvironmental factors (e.g. nutrient deprivation, hypoxia) or to the effects of anti-cancer treatments (e.g. chemotherapy, radiotherapy). As almost all mitochondrial proteins are nuclear-encoded and imported into the organelle, specialized import machineries have evolved in order to meet the need for protein import. Among these machineries, the one that operates in the intermembrane space and is controlled by CHCHD4/Mia40, regulates the import of a group of proteins (substrates) that play important roles in survival and stress response. Substrates of CHCHD4/Mia40 are involved in a broad panel of mitochondrial activities that includes the biogenesis of respiratory chain complexes, lipid homeostasis, calcium storage, as well as ultrastructure and mitochondrial dynamics. This thesis program was dedicated to the study of the CHCHD4/Mia40 import pathway in cancer cells, with a particular interest for one of the CHCHD4/Mia40 substrates that shapes mitochondrial ultrastructure. Using RNA interference approach and recombinant protein overexpression technique, in a colon cancer model, we showed that the expression of this substrate had a crucial effect on proliferation and tumor growth. Our data also involved this protein in the response to anti-cancer treatments. All together, this work opens a new field of investigations that will not only shed new lights on the metabolic plasticity of cancer cells but also help to identify new metabolic biomarkers
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Peguillet, Isabelle. "Lymphocytes T CD4 et immunité anti-tumorale naturelle : impact de la chimiothérapie, émergence de lymphocytes T CD4 cytotoxiques." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T034/document.
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Historiquement, les LT CD8 cytotoxiques ont été considérés comme la seule composante cellulaire du système immunitaire nécessaire et suffisante pour l’élimination de cellules infectées par des virus ou transformées, les LT CD4 ne jouant qu’un rôle auxiliaire, dans le développement et le maintien de la réponse immune effectrice, ou modulateur par la fonction suppressive des T-Reg. Aux côtés, de ces fonctions auxiliaires ou suppressive, nombre de données indiquaient que les LT CD4 pouvaient également exercer une activité cytotoxique directe. Nos travaux ont permis par l’analyse chez l’Homme, de l’expression des récepteurs α à l’IL-2 (CD25) et à l’IL-7 (CD127) à la surface des LT CD4 du sang périphérique d’identifier une population singulière de LT CD4 caractérisée par l’absence de ces deux molécules. Ces LT CD4, CD25-CD127-, faiblement représentées chez les sujets sains, entre 0,2-2% des LT CD4 totaux du sang périphérique, étaient fortement augmentées, entre 2-20% dans les infections chroniques VIH et Tuberculose, et notamment dans les cancers incluant les mélanomes uvéaux métastatiques (Mum) et les cancers du sein. Puisque prédominant dans des situations de stimulation chronique, ces LT CD4 ont été définis comme des LT CD4 chroniquement stimulés : chCD4. Dans le sang périphérique de patients atteints de cancer comme chez les sujets sains, la majorité de ces chCD4 arboraient un phénotype mémoire/effecteur (CD45RO+). Cependant, dans les Mum et les cancers du sein la proportion de chCD4 effecteurs (CD45RO+CD27-) était fortement augmentée. Par ailleurs, si la plus part de ces cellules effectrices apparaissaient à un stade de différenciation terminale (CD57+), elles présentaient toutes les mêmes caractéristiques phénotypiques distinctes, définies par l’absence d’expression de la molécule de co-stimulation CD28 coordonnée à l’expression à leur surface de l’intégrine CD11b et du récepteur NK, 2B4. Dans les chCD4 effecteurs, nous avons également mis en évidence la présence spécifique de granules cytoplasmiques concentrant granzyme B et perforine, molécules impliquées dans la cytotoxicité directe de cellules cibles. Cette propriété fonctionnelle a été démontrée par des tests de cytotoxicité redirigée et était restreinte aux chCD4 effecteurs en comparaison aux autres sous-populations effectrices de LT CD4 conventionnels et T-Reg. L’analyse du profile de sécrétion de cytokines, révèle l’absence total de production d’IL-17 et un profile orienté Th1, soulevant la question du lignage de cette population particulière. L’absence d’expression de Ki67, marqueur des cellules en cycle, au sein de cette population de LT CD4 cytotoxiques, parallèlement à leur accumulation, suggérait qu’elles seraient capables de persister à l’état quiescent chez les patients. Par ailleurs, dans les Mum, nous avons mis en évidence que l’augmentation importante du nombre de chCD4 chez les patients, concordait avec la présence d’expansions oligoclonales au sien de cette population, et démontré une corrélation positive entre le pourcentage des cellules effectrices, chCD4 et LT CD8, LT CD8 parmi lesquels nous avons déterminé une fréquence élevée de cellules répondeuses spécifiques d’antigènes tumoraux associés à la tumeur. Nos travaux ont également permis d’évaluer l’impact de la chimiothérapie sur les populations lymphocytaires dans le sang périphérique. Chez les patientes atteintes de cancer du sein, traitées par chimiothérapie néo-adjuvante, c’est-à-dire préopératoire, nous avons constaté une augmentation du nombre de chCD4 chez 17/22 patientes. Nous avons mis en évidence que cette augmentation sous traitement était fortement corrélée au pourcentage de régression tumorale. L’ensemble de ces résultats apporte une nouvelle vision des LT CD4 dans l’immunité tumorale. (...)Historically, CD8 positive Cytotoxic T Lymphocytes (CTL) have been associated with an effector immune response, while T cells with a CD4 phenotype where considered helper T cells. More recent data suggest that CD4 positive T cells are also capable of a direct cytotoxic activity. Through a systematic analysis of the IL-2 (CD25) as well as IL-7 (CD127) receptors α on the surface of CD4+ CTL in peripheral blood of patients before during and after treatment we were able to identify a specific CD4+ T cell population devoid of expression for these 2 molecules. These CD4+, CD25-CD127-, T cells only represent 0,2-2% of the total CD4+ pool in peripheral blood of healthy donors, while in the presence of a chronic infectious disease such as HIV or tuberculosis they were increased, representing up to 2-20% of all CD4+ T cells. Similarly, high numbers of CD4+, CD25-CD127-, T cells could be identified in the circulation in patients with metastatic uveal melanoma (muM) or with breast cancer. These chronically stimulated T cells (chCD4) demonstrate a memory effector phenotype (CD45RO+); while the majority shows a terminally differentiated phenotype (CD57+), these T cells all arbore distinct phenotypic characteristics as defined by the absence of expression of CD28 together with the presence of a surface expression of integrin CD11b and of the NK receptor, 2B4. The presence of cytoplasmic granules concentrating granzyme B and perforin, known to be responsible for T cell cytotoxicity, were identified in effector chCD4 while they were absent in conventional CD4+ T cells as well as in Tregs. This cytotoxic potential was demonstrated through redirected cytotoxicity assays that functionally confirm this feature of these chronically activated CD4+ T cells. The secretory cytokine profile showed absent IL-17 levels and a Th1 orientation, asking questions as regards to the lineage of this particular T cell population. Ki67 expression, a marker of cell proliferation, was absent, suggestive of their ability to persist quiescently in patients. However in muM patients we were able to demonstrate a vast oligoclonal increase in chCD4+ T cells, which correlated positively with CD8+ T cells. We were able to detect a high frequency of T cells responding against a specific tumor antigen among these CD8+ T cells. We furthermore studied the effects of chemotherapy on peripheral lymphocyte populations. In breast cancer patients who had been treated with preoperative (neoadjuvant) chemotherapy we detected high levels of effector chCD4 in 17/22 patients. Of particular interest was the fact that this increase through a course of chemotherapy treatment was strongly correlated to the percentage of regression of the original tumor. Together, these results cast new light on the role and function of CD4+ T cells in tumor immunity. Our observations show that CD4+ cytotoxic T lymphocytes do exist and suggest for the first time in human that they may have an important role in response to treatment and in particular in the establishment of a durable protective immune response
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Bourefis, Annis-Rayan. "Novel FUS and CHCHD10 models to investigate pathogenic mechanisms in Amyotrophic Lateral Sclerosis." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS177.
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La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative dévastatrice causée par la dégénérescence progressive des motoneurones (MNs) supérieurs et inférieurs menant à une faiblesse et une atrophie musculaire qui progresse jusqu’à la paralysie. Deux gènes majeurs identifiés chez les patients SLA sont le gène FUS (FUSed in sarcoma), impliqué dans le métabolisme de l’ARN, et CHCHD10, qui joue un rôle dans la stabilité des mitochondries. Ces deux gènes ont été étudiés à travers différents modèles, de petits modèles invertébrés aux biopsies de patients. Cependant, les différents traits phénotypiques observés sont complexes et parfois controversés. L’objectif de cette thèse est de fournir de nouvelles informations sur l’implication de ces deux gènes dans la SLA à travers l’utilisation de nouveaux modèles. Pour étudier les mécanismes pathologiques induits par FUS et CHCHD10, nous avons généré et caractérisé deux nouveaux modèles de poisson-zèbres présentant une mutation non-sens des orthologues de ces gènes, et nous avons mis en évidence différents traits phénotypiques propres à la SLA. Nous avons montré, pour FUS, une espérance de vie réduite, une locomotion altérée, des axones moteurs aberrants, une jonction neuromusculaire (JNM) désorganisée, une altération des muscles et mitochondries, ainsi que des changements moléculaires. Ces résultats montrent que la perte de fonction de fus est responsable de l’apparition de signes pathologiques distaux au niveau de la JNM, indiquant une neuronopathie en « dying-back », dans laquelle les traits pathologiques de la SLA commencent au niveau de la JNM et progressent vers les corps cellulaires des MNsAmyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder caused by progressive degeneration of upper and lower motor neurons (MNs), with a very rapid clinical course. It leads to muscle weakness and atrophy progressing to paralysis, with respiratory failure being the major cause of death within years following clinical diagnosis. Two major genes mutated in ALS patients are the RNA-binding protein FUS (FUSed in sarcoma), implicated in RNA metabolism, and coiled-coil-helix-coiled-coil-helix domain 10 (CHCHD10), which plays a role in mitochondria stability. Both these genes have been investigated through different model systems, from small invertebrate models to patient biopsies. However, the major phenotypic features obtained in these models are complex and often controversial. The objective of this work is to provide new insights on the implication of these genes in ALS through the use of new models.To investigate the pathogenic mechanisms induced by FUS and CHCHD10, we generated and characterized two novel stable non-sense mutant zebrafish models for the orthologues of these genes and highlighted several ALS phenotypic features. We demonstrated, for the FUS model but not for CHCHD10, reduced lifespan, locomotor disabilities, aberrant motor axons, disorganized neuromuscular junction (NMJ), muscle and mitochondrial alteration, as well as molecular changes. These findings indicate that loss of fus expression is responsible for the occurrence of distal pathological signs at the NMJ, thus supporting a “dying-back” neuronopathy, in which early disease hallmarks start at the level of the NMJ and progress towards MN cell bodies
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Teyssou, Elisa. "Analyses génétiques et fonctionnelles de nouveaux gènes incriminés dans la Sclérose Latérale Amyotrophique (SLA) Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients Genetic analysis of CHCHD10 in French familial amyotrophic lateral sclerosis patients." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066738.
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La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative fatale caractérisée par la dégénérescence des motoneurones centraux et périphériques. Elle est le plus souvent sporadique (SALS, 90% des cas), tandis que les formes familiales (FALS) représentent 10% des patients. Une vingtaine de gènes liés à la SLA ont été identifiés et sont responsables de 70% des FALS et 10% des SALS. Le but de ce projet était d’étudier la contribution de 6 gènes rares dans une large cohorte de patients français atteints de SLA et d’étudier les conséquences fonctionnelles de certains variants identifiés. La première partie de ce projet a consisté à réaliser l’analyse génétique des gènes MATR3, CHCHD10, SS18L1, SQSTM1, UBQLN2 et PFN1. Aucun variant causal ne fut identifié pour les 2 premiers gènes alors que 2 nouveaux variants possiblement pathogènes ont été identifiés dans le gène SS18L1, 4 mutations pour SQSTM1, 5 dans UBQLN2 et 2 mutations déjà répertoriées dans le gène PFN1. Cette analyse génétique a permis de souligner un chevauchement génétique entre SLA et maladie de Paget pour SQSTM1 et entre SLA et Paraplégie Spastique pour UBQLN2. La deuxième partie de ce projet a consisté en l’étude de la pathogénicité de certains variants que nous avons identifiés dans les gènes SQSTM1, UBQLN2 et PFN1, par l’analyse (i) des inclusions dans les tissus post mortem de patients, (ii) de l’expression et de la dégradation protéique dans des lymphoblastes issus de patients SLA et/ou (iii) des conséquences cellulaires après surexpression in vitro et in vivo. Ces analyses ont montré, concernant SQSTM1, qui est impliquée dans la formation des autophagosomes, que les mutations perturbaient l’agrégation protéique, que les mutations dans le gène UBQLN2 altéraient la dégradation lysosomale et la liaison de la protéine avec HSP70 et que celles dans PFN1 dérégulaient la voie de l’autophagie alternative et la mitophagie. Notre travail a permis (i) d’évaluer la contribution chez les patients français atteints de SLA de plusieurs gènes incriminés dans la SLA, (i) d’élargir le spectre génétique commun à la SLA et à d’autres pathologies et (iii) de mettre en avant la pertinence de l’implication des voies de dégradation protéique, notamment l’autophagie, dans la pathogénèse de la maladieThe fatal Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is characterized by the degeneration of upper and lower motor neurons. Most ALS cases are sporadic (SALS) whereas ~10% are familial (FALS). A growing number of genes has been identified in ALS and represent 70% of FALS and 10% of SALS. The aims of this project were to analyze the contribution of 6 rare genes in a large population of French ALS patients and to study the pathogenic impact of some identified variants.The first part of this work was dedicated to the genetic analysis of MATR3, CHCHD10, SS18L1, SQSTM1, UBQLN2 and PFN1 genes. No causing variants were identified for MATR3 and CHCHD10 while 2 new variants, probably pathogenic, were identified for SS18L1, as well as 4 mutations for SQSTM1, 5 for UBQLN2 and 2 already reported mutations for PFN1. These analyses also highlighted a genetic overlap between ALS and other diseases: the Paget disease of bone for SQSTM1 and spastic paraplegia for UBQLN2. The second part of this work was to study the pathogenicity of some of the mutations identified in SQSTM1, UBQLN2 and PFN1 genes using analyses of (i) inclusions in ALS patient post-mortem tissue, (ii) protein expression and degradation pathways in patient lymphoblasts and/or (iii) cellular consequences after in vitro and in vivo overexpression. Our results showed prominent aggregation of mutant SQSTM1 (involved in autophagosomes formation), impaired lysosomal degradation and disrupted protein binding to HSP70 for mutant UBQLN2 and deregulated alternative autophagy and mitophagy pathways for mutant PFN1. Our results (i) precised the contribution of several genes in French ALS patients, (i) documented the genetic overlap between ALS and other diseases and (iii) highlighted the role of protein degradation pathways, especially autophagy, in the pathogenesis of ALS
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Niccolai, Gerald Peter. "I. Fenske-Hall molecular orbital studies of [CpM(CO)n]₂ complexes the interplay of metal-metal bonding and bridging and semibridging ligands : II. The photolytic dehydrogenation of the diiron alkylidene complex, [CpFe(CO)]₂([mu]-CO)([mu]-CHCH₂CH₂CH₂CH₃) /." 1992. http://catalog.hathitrust.org/api/volumes/oclc/31370805.html.
Full textBooks on the topic "CHCHD4"
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Torbokov, Tokshyn, and R. A. Lykova. Altaĭ u̇lgerlik XIX-XXI chch. Gorno-Altaĭsk: U̇ch-Su̇mer, 2006.
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Huang, Jinfan. Gaseous electron-diffraction investigations: I. Molecular structures of Os(CO)₅, Ru(CO)₅, and CrOF₄. II. Molecular structures and anti-gauche compositions of BrCH₂,CH₂,F, BrCH₂CH₂C1, C1CH₂CH₂F,C1₂CHCHC1₂, and FCH₂CH₂OH. 1989.
Find full textBook chapters on the topic "CHCHD4"
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Weiner, John. "Atom traps and studies of ultracold systems." In Encyclopedia of Chemical Physics and Physical Chemistry - 3 Volume Set. Taylor & Francis, 2001. http://dx.doi.org/10.1201/9781420050721.chc1.4.
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Hahner, Georg. "Organic films (Langmuir-Blodgett films and self-assembled monolayers)." In Encyclopedia of Chemical Physics and Physical Chemistry - 3 Volume Set. Taylor & Francis, 2001. http://dx.doi.org/10.1201/9781420050721.chc2.4.
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Demidov, Andrey, and David Andrews. "Electronic energy transfer in condensed phases." In Encyclopedia of Chemical Physics and Physical Chemistry - 3 Volume Set. Taylor & Francis, 2001. http://dx.doi.org/10.1201/9781420050721.chc3.4.
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Bottura, L. "Quench propagation and protection of cable-in-conduit superconductors." In Handbook of Applied Superconductivity, Volume 2, 557–72. Taylor & Francis, 1998. http://dx.doi.org/10.1201/9781420050271.chc4.
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Sastry, P., and C. Buzea. "HgBCCO." In Handbook of Superconducting Materials, 1029–48. Taylor & Francis, 2002. http://dx.doi.org/10.1201/9781420034202.chc4.
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"(and ALKYLALUMINUMS generally) [(CH )CHCH]AlH." In Hazardous Laboratory Chemicals Disposal Guide, 267–68. CRC Press, 1996. http://dx.doi.org/10.1201/b12375-20.
Full textConference papers on the topic "CHCHD4"
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Souto, Emília Correia, Carolina Maria Marin, Gustavo Carvalho Costa, Igor Braga Farias, Bruno de Mattos Lombardi Badia, Icaro França Navarro Pinto, Roberta Ismael Lacerda Machado, Paulo Victor Sgobbi de Souza, Wladimir Bocca Vieira de Rezende Pinto, and Acary Souza Bulle Oliveira. "Family with atypical Parkinsonism due to CHCHD10 gene mutation." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.502.
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Introduction: Parkinson’s disease - PD is the second most common agerelated neurodegenerative disorder. Characterized by a variety of motor and non-motor symptoms that relate to the loss of dopaminergic neurons in the midbrain black substance. Although most cases of PD are sporadic, 5–10% of patients have monogenetic mutations with a description of more than 20 genes for the familial form. Mitochondrial mutation in CHCHD10 has also been reported to be associated with a wide spectrum of neurodegenerative disorders, including PD. Objectives: Description of a rare recently described genetic cause of autosomal dominant parkinsonism. Methodology: Describe the case of a Brazilian woman with atypical parkinsonism due to CHCHD10 pathogenic variant that was followed up in our service. Result: Female, 64 years old. “. He started episodes of imbalance about 5 years ago, with falls, in addition to limb stiffness, worse on the left. 4 years ago, he started myalgia to great efforts with low subsequent tolerance to light effort. 1 year ago with urinary incontinence and choking past of poor performance in physical activities without pre-motor symptoms FAMILY: mother with clinical picture of possible dementia syndrome at age 60, history in the maternal family of myalgia, intolerance to physical exercise and hearing loss in adulthood. EXOMA: presence of variant c.146C > T (p.Ala49Val) in simple heterozygosity without CHCHD10 gene. MRI with thigh muscle hypotrophy in anterior and posterior thigh compartments; slight muscle edema in the legs. Conclusion: Pathogenic variants in the CHCHD10 gene should be considered in cases of atypical parkinsonism, especially in cases of positive familial history of mitochondrial myopathy or dementia.
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Lumibao, Jan C., and H. Rex Gaskins. "Abstract 2650: Characterizing CHCHD2 subcellular localization in response to hypoxia and redox perturbations in glioblastoma cells." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2650.
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Lumibao, Jan C., and H. Rex Gaskins. "Abstract 2650: Characterizing CHCHD2 subcellular localization in response to hypoxia and redox perturbations in glioblastoma cells." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2650.
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Masi, Silvia, Claudio Molaschi, Fabrizio Zausa, and Jean Michelez. "Managing Circulation Losses in a Harsh Drilling Environment: Conventional Solution vs. CHCD Through a Risk Assessment." In IADC/SPE Drilling Conference and Exhibition. Society of Petroleum Engineers, 2010. http://dx.doi.org/10.2118/128225-ms.
Full textReports on the topic "CHCHD4"
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Wei, Huijie, Xin Mu, Yu Li, Hua Lei, De Yang, Tian Li, and Junwei Ren. Meta-analysis of the association between CHCHD10 Pro34Ser variant and the risk of frontotemporal dementia. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, May 2021. http://dx.doi.org/10.37766/inplasy2021.5.0090.
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