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5. Alteration of cGAS-STING signaling pathway components in the mouse cortex and hippocampus during healthy brain aging.

Author

Passarella, Sergio, Kethiswaran, Shananthan, Brandes, Karina, I.-Chin Tsai, Cebulski, Kristin, Kröger, Andrea, Dieterich, Daniela C., and Landgraf, Peter

Subjects
HIPPOCAMPUS physiology, RESEARCH funding, AUTOPHAGY, T-test (Statistics), HOMEOSTASIS, BRAIN, CELLULAR aging, NEURONS, NEUROGLIA, ENZYME-linked immunosorbent assay, PROBABILITY theory, CELLULAR signal transduction, NEURODEGENERATION, REVERSE transcriptase polymerase chain reaction, DESCRIPTIVE statistics, TEMPORAL lobe, MICE, IMMUNOHISTOCHEMISTRY, MEMORY, ANIMAL experimentation, DNA damage, WESTERN immunoblotting, SPACE perception, NATURAL immunity, INFLAMMATION, MICROSCOPY, DATA analysis software, MEMBRANE proteins, CELLS, IMMUNOBLOTTING
Abstract

The cGAS-STING pathway is a pivotal element of the innate immune system, recognizing cytosolic DNA to initiate the production of type I interferons and pro-inflammatory cytokines. This study investigates the alterations of the cGASSTING signaling components in the cortex and hippocampus of mice aged 24 and 108 weeks. In the cortex of old mice, an increase in the dsDNA sensor protein cGAS and its product 2030-cGAMP was observed, without corresponding activation of downstream signaling, suggesting an uncoupling of cGAS activity from STING activation. This phenomenon may be attributed to increased dsDNA concentrations in the EC neurons, potentially arising from nuclear DNA damage. Contrastingly, the hippocampus did not exhibit increased cGAS activity with aging, but there was a notable elevation in STING levels, particularly in microglia, neurons and astrocytes. This increase in STING did not correlate with enhanced IRF3 activation, indicating that brain inflammation induced by the cGAS-STING pathway may manifest extremely late in the aging process. Furthermore, we highlight the role of autophagy and its interplay with the cGAS-STING pathway, with evidence of autophagy dysfunction in aged hippocampal neurons leading to STING accumulation. These findings underscore the complexity of the cGASSTING pathway's involvement in brain aging, with regional variations in activity and potential implications for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Braun, Alice, Kraft, Julia, Skarabis, Nora, Walter, Henrik, Ripke, Stephan, Pardiñas, Antonio F., Dennison, Charlotte A., Hall, Lynsey S., Harwood, Janet C., Richards, Alexander L., Legge, Sophie E., Lynham, Amy, Williams, Nigel M., Bray, Nicholas J., Escott-Price, Valentina, Kirov, George, Holmans, Peter A., Pocklington, Andrew J., Owen, Michael J., Walters, James T. R., O’Donovan, Michael C., Qi, Ting, Sidorenko, Julia, Wu, Yang, Zeng, Jian, Gratten, Jacob, Visscher, Peter M., Yang, Jian, Wray, Naomi R., Bigdeli, Tim B., Fanous, Ayman H., Bryois, Julien, Bergen, Sarah E., Kähler, Anna K., Magnusson, Patrik K. E., Hultman, Christina M., Sullivan, Patrick F., Chen, Chia-Yen, Atkinson, Elizabeth G., Goldstein, Jacqueline I., Howrigan, Daniel P., Martin, Alicia R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Ge, Tian, Lam, Max, Belliveau, Richard A., Chambert, Kimberley D., Genovese, Giulio, Lee, Phil H., Pietiläinen, Olli, McCarroll, Steven A., Moran, Jennifer L., Smoller, Jordan W., Brown, Tyler C., Feng, Guoping, Hyman, Steven E., Sheng, Morgan, Chong, Siow Ann, Subramaniam, Mythily, Lencz, Todd, Malhotra, Anil K., Watanabe, Kyoko, Frei, Oleksandr, Agartz, Ingrid, Athanasiu, Lavinia, Melle, Ingrid, Andreassen, Ole A., Steen, Nils Eiel, DeLisi, Lynn E., Mesholam-Gately, Raquelle I., Seidman, Larry J., Koopmans, Frank, Magnusson, Sigurdur, Stefánsson, Hreinn, Stefansson, Kari, Grove, Jakob, Agerbo, Esben, Als, Thomas D., Bybjerg-Grauholm, Jonas, Demontis, Ditte, Hougaard, David M., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Børglum, Anders D., Mattheisen, Manuel, Kim, Minsoo, Gandal, Michael J., Li, Zhiqiang, Shi, Yongyong, Zhou, Wei, Qin, Shengying, Voloudakis, Georgios, Zhang, Wen, Roussos, Panos, Adams, Mark, McIntosh, Andrew, Söderman, Erik, Jönsson, Erik G., McGrath, John J., Al Eissa, Mariam, Bass, Nicholas J., Fiorentino, Alessia, O’Brien, Niamh Louise, Pimm, Jonathan, Sharp, Sally Isabel, McQuillin, Andrew, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Bruggeman, Richard, Alptekin, Köksal, Amin, Farooq, Arolt, Volker, Lencer, Rebecca, Rothermundt, Matthias, Baune, Bernhard T., Arrojo, Manuel, Azevedo, Maria Helena, Bacanu, Silviu A., Webb, Bradley T., Wormley, Brandon K., Riley, Brien P., Kendler, Kenneth S., Begemann, Martin, Mitjans, Marina, Steixner-Kumar, Agnes A., Ehrenreich, Hannelore, Bene, Judit, Benyamin, Beben, Blasi, Giuseppe, Rampino, Antonio, Torretta, Silvia, Bertolino, Alessandro, Bobes, Julio, Bonassi, Stefano, Bressan, Rodrigo Affonseca, Gadelha, Ary, Noto, Cristiano, Ota, Vanessa Kiyomi, Santoro, Marcos Leite, Belangero, Sintia Iole, Bromet, Evelyn J., Buckley, Peter F., Buckner, Randy L., Cahn, Wiepke, Kahn, René S., Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Schall, Ulrich, Calkins, Monica E., Gur, Raquel E., Gur, Ruben C., Turetsky, Bruce I., Carr, Vaughan J., Castle, David, Harvey, Carol, Catts, Stanley V., Chan, Raymond C. K., Chaumette, Boris, Kebir, Oussama, Krebs, Marie-Odile, Cheng, Wei, Cheung, Eric F. C., Cohen, David, Consoli, Angèle, Giannitelli, Marianna, Laurent-Levinson, Claudine, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Quattrone, Diego, Breen, Gerome, Collier, David A., Di Forti, Marta, Vassos, Evangelos, Mondelli, Valeria, van Amelsvoort, Therese, Murray, Robin M., Davidson, Michael, Davis, Kenneth L., Haroutunian, Vahram, Malaspina, Dolores, Reichenberg, Abraham, Siever, Larry J., Silverman, Jeremy M., Buxbaum, Joseph D., de Haan, Lieuwe, Degenhardt, Franziska, Forstner, Andreas, Nöthen, Markus M., Dickerson, Faith, Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Gejman, Pablo V., Sanders, Alan R., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Peñas, Javier González, González-Pinto, Ana, Molto, María Dolores, Moreno, Carmen, Parellada, Mara, Sanjuan, Julio, Crepo-Facorro, Benedicto, Mata, Ignacio, Arango, Celso, Faraone, Stephen V., Frank, Josef, Streit, Fabian, Witt, Stephanie H., Rietschel, Marcella, Freimer, Nelson B., Ophoff, Roel A., Fromer, Menachem, Stahl, Eli A., Frustaci, Alessandra, Gershon, Elliot S., Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Giusti-Rodríguez, Paola, Szatkiewicz, Jin P., Godard, Stephanie, González Peñas, Javier, Gopal, Srihari, Savitz, Adam, Li, Qingqin S., Green, Michael F., Nuechterlein, Keith H., Sugar, Catherine A., Greenwood, Tiffany A., Light, Gregory A., Swerdlow, Neal R., Braff, David, Guillin, Olivier, Campion, Dominique, Gülöksüz, Sinan, Luykx, Jurjen J., Rutten, Bart P. F., van Winkel, Ruud, Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Pellegrino, Renata, Pantelis, Christos, Hayward, Caroline, Henskens, Frans A., Kelly, Brian J., Herms, Stefan, Hoffmann, Per, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, van Os, Jim, Joa, Inge, Julià, Antonio, Marsal, Sara, Kam-Thong, Tony, Rautanen, Anna, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Toncheva, Draga, Keller, Matthew C., Khrunin, Andrey, Limborska, Svetlana, Slominsky, Petr, Kim, Sung-Wan, Klovins, Janis, Nikitina-Zake, Liene, Kondratiev, Nikolay, Golimbet, Vera, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Levinson, Douglas F., Petryshen, Tracey L., Lehrer, Douglas S., Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Stroup, T. Scott, Liu, Chih-Min, Hwu, Hai-Gwo, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Bakker, Steven, Kahn, René, Macek, Milan, Mackinnon, Andrew, Maher, Brion S., Maier, Wolfgang, Atbaşoğlu, Eşref Cem, Mallet, Jacques, Marder, Stephen R., Martorell, Lourdes, Muntané, Gerard, Vilella, Elisabet, Meier, Sandra, Schulze, Thomas G., McCarley, Robert W., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Periyasamy, Sathish, Mowry, Bryan J., Medeiros, Helena, Sobell, Janet L., Melegh, Bela, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Michie, Patricia T., Milanova, Vihra, Molden, Espen, Molina, Esther, Morley, Christopher P., Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Pulver, Ann E., O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Freedman, Robert, Paunio, Tiina, Perkins, Diana O., Pfuhlmann, Bruno, Benner, Christian, Pirinen, Matti, Palotie, Aarno, Porteous, David, Powell, John, Quested, Digby, Radant, Allen D., Tsuang, Debby W., Rapaport, Mark H., Roe, Cheryl, Liu, Chunyu, Roffman, Joshua L., Roth, Julian, Gawlik, Micha, Saker-Delye, Safaa, Salomaa, Veikko, Suvisaari, Jaana, Shi, Jianxin, Sigurdsson, Engilbert, Sim, Kang, So, Hon-Cheong, Stain, Helen J., Stögmann, Elisabeth, Zimprich, Fritz, Stone, William S., Straub, Richard E., Hyde, Thomas, Jaffe, Andrew, Weinberger, Daniel R., Strengman, Eric, Svrakic, Dragan M., Cloninger, C. Robert, Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Tosato, Sarah, Tura, Gian Battista, Üçok, Alp, Vaaler, Arne, Veijola, Juha, Waddington, John, Waterreus, Anna, Morgan, Vera A., Jablensky, Assen V., Weiser, Mark, Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Kennedy, James L., Zhu, Feng, Saka, Meram C., Ayub, Muhammad, Black, Donald W., Buccola, Nancy G., Byerley, William F., Chen, Wei J., Crespo-Facorro, Benedicto, Galletly, Cherrie, Gennarelli, Massimo, Müller-Myhsok, Bertram, Neil, Amanda L., Pato, Michele T., Pato, Carlos N., Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Bramon, Elvira, Cervilla, Jorge A., Cichon, Sven, Corvin, Aiden, Gill, Michael, Curtis, David, Domenici, Enrico, Gareeva, Anna, Khusnutdinova, Elza, Glatt, Stephen J., Hong, Kyung Sue, Knowles, James A., Lee, Jimmy, Liu, Jianjun, Malhotra, Dheeraj, Menezes, Paulo R., Nimgaonkar, Vishwajit, Paciga, Sara A., Rivera, Margarita, Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Clair, David St, Tsuang, Ming T., Vawter, Marquis P., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Verhage, Matthijs, Sahasrabudhe, Dnyanada, Toonen, Ruud F., Posthuma, Danielle, Dai, Nan, Wenwen, Qin, Wildenauer, D. B., Agiananda, Feranindhya, Amir, Nurmiati, Antoni, Ronald, Arsianti, Tiana, Asmarahadi, Asmarahadi, Diatri, H., Djatmiko, Prianto, Irmansyah, Irmansyah, Khalimah, Siti, Kusumadewi, Irmia, Kusumaningrum, Profitasari, Lukman, Petrin R., Nasrun, Martina W., Safyuni, N. S., Prasetyawan, Prasetyawan, Semen, G., Siste, Kristiana, Tobing, Heriani, Widiasih, Natalia, Wiguna, Tjhin, Wulandari, D., Evalina, None, Hananto, A. J., Ismoyo, Joni H., Marini, T. M., Henuhili, Supiyani, Reza, Muhammad, Yusnadewi, Suzy, Abyzov, Alexej, Akbarian, Schahram, van Bakel, Harm, Breen, Michael, Charney, Alex, Dracheva, Stella, Girdhar, Kiran, Hoffman, Gabriel, Jiang, Yan, Pinto, Dalila, Purcell, Shaun, Roussos, Panagiotis, Wiseman, Jennifer, Ashley-Koch, Allison, Crawford, Gregory, Reddy, Tim, Brown, Miguel, Grennan, Kay, Carlyle, Becky, Emani, Prashant, Galeev, Timur, Gerstein, Mark, Gu, Mengting, Guerra, Brittney, Gursoy, Gamze, Kitchen, Robert, Lee, Donghoon, Li, Mingfeng, Liu, Shuang, Navarro, Fabio, Pan, Xinghua, Pochareddy, Sirisha, Rozowsky, Joel, Sestan, Nenad, Sethi, Anurag, Shi, Xu, Szekely, Anna, Wang, Daifeng, Warrell, Jonathan, Weissman, Sherman, Wu, Feinan, Xu, Xuming, Coetzee, Gerard, Farnham, Peggy, Lay, Fides, Rhie, Suhn, Witt, Heather, Wood, Shannon, Yao, Lijing, Gandal, Mike, Polioudakis, Damon, Swarup, Vivek, Won, Hyejung, Giase, Gina, Jiang, Shan, Kefi, Amira, Shieh, Annie, Goes, Fernando, Zandi, Peter, Kim, Yunjung, Mattei, Eugenio, Purcaro, Michael, Pratt, Henry, Peters, Mette A., Sanders, Stephan, Weng, Zhiping, White, Kevin, Arranz, Maria J., Lewis, Cathryn, Lin, Kuang, Walshe, Muriel, Bender, Stephan, Weisbrod, Matthias, Hall, Jeremy, Lawrie, Stephen, Linszen, Don H., Achsel, Tilmann, Bagni, Claudia, Andres-Alonso, Maria, Kreutz, Michael R., Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Coba, Marcelo P., Cornelisse, L. Niels, van Weering, Jan R. T., de Jong, Arthur P. H., MacGillavry, Harold D., de Juan-Sanz, Jaime, Dieterich, Daniela C., Pielot, Rainer, Smalla, Karl-Heinz, Gundelfinger, Eckart D., Goldschmidt, Hana L., Huganir, Richard L., Hoogenraad, Casper, Imig, Cordelia, Jahn, Reinhard, Jung, Hwajin, Kim, Eunjoon, Kaeser, Pascal S., Lipstein, Noa, Malenka, Robert, McPherson, Peter S., O’Connor, Vincent, Ryan, Timothy A., Sala, Carlo, Verpelli, Chiara, Smit, August B., Südhof, Thomas C., Thomas, Paul D., Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Internal medicine, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Psychiatrie (3), MUMC+: MA Med Staf Spec Psychiatrie (9), MUMC+: Hersen en Zenuw Centrum (3), Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Benyamin, Beben, O'Donovan, Michael C, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Molecular and Cellular Neurobiology, Functional Genomics, and Complex Trait Genetics

Subjects
Genetics of the nervous system, Schizophrenia/genetics, VARIANTS, PROFILE, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, DISEASE, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Alleles, Genomics, Genome-Wide Association Study, Schizophrenia, Polymorphism, RISK, ARCHITECTURE, Science & Technology, Multidisciplinary, MUTATIONS, Genetic Predisposition to Disease/genetics, Settore BIO/13, Single Nucleotide, ASSOCIATION, Polymorphism, Single Nucleotide/genetics, STATISTICS, Multidisciplinary Sciences, INDIVIDUALS, Science & Technology - Other Topics, Diseases of the nervous system, ddc:500, Single Nucleotide/genetics, INTEGRATION
Abstract

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., The work at Cardiff University was additionally supported by Medical Research Council Centre grant no. MR/L010305/1 and program grant no. G0800509. S. Xu also gratefully acknowledges the support of the National Natural Science Foundation of China (NSFC) grants (31525014, 91731303, 31771388, 31961130380 and 32041008), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) and the Strategic Priority Research Program (XDB38000000) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). O. A. Andreassen was supported by the Research Council of Norway (283798, 262656, 248980, 273291, 248828, 248778, 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, EU H2020 no. 847776. B. Melegh was supported in part by the National Scientific Research Program (NKFIH) K 138669. S. V. Faraone is supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreements 667302 and 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. S. I. Belangero was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), grant numbers: 2010/08968-6; 2014/07280-1 2011/50740-5 (including R. A. Bressan). The Singapore team (J. Lee, J. Liu, K. Sim, S. A. Chong and M. Subramanian) acknowledges the National Medical Research Council Translational and Clinical Research Flagship Programme (grant no.: NMRC/TCR/003/2008). M. Macek was supported by LM2018132, CZ.02.1.01/0.0/0.0/18_046/0015515 and IP6003 –VZFNM00064203. C. Arango has been funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no 115916, project PRISM; and grant agreement no. 777394, project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. E. Bramon acknowledges support from the National Institute of Health Research UK (grant NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; an ESRC collaborative award 2020; BMA Margaret Temple Fellowship 2016; Medical Research Council New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; National Institute of Health Research UK post-doctoral fellowship (PDA/02/06/016); NARSAD Young Investigator awards 2005 and 2008; Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z, 085475/Z/08/Z); European Commission Horizon 2020 (747429); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London; and NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (UCLH BRC - Mental Health Theme). D. Molto is funded by the European Regional Development Fund (ERDF)–Valencian Community 2014–2020, Spain. E. G. Atkinson was supported by the NIMH K01MH121659.

Published
2022

22. A role for TASK2 channels in the human immunological synapse

Author

Fernández‐Orth, Juncal, primary, Rolfes, Leoni, additional, Gola, Lukas, additional, Bittner, Stefan, additional, Andronic, Joseph, additional, Sukhorukov, Vladimir L., additional, Sisario, Dmitri, additional, Landgraf, Peter, additional, Dieterich, Daniela C., additional, Cerina, Manuela, additional, Smalla, Karl‐Heinz, additional, Kähne, Thilo, additional, Budde, Thomas, additional, Kovac, Stjepana, additional, Ruck, Tobias, additional, Sauer, Markus, additional, and Meuth, Sven G., additional

Published
2020
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23. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse

Author

Sub Cell Biology, Celbiologie, Koopmans, Frank, van Nierop, Pim, Andres-Alonso, Maria, Byrnes, Andrea, Cijsouw, Tony, Coba, Marcelo P, Cornelisse, L Niels, Farrell, Ryan J, Goldschmidt, Hana L, Howrigan, Daniel P, Hussain, Natasha K, Imig, Cordelia, de Jong, Arthur P H, Jung, Hwajin, Kohansalnodehi, Mahdokht, Kramarz, Barbara, Lipstein, Noa, Lovering, Ruth C, MacGillavry, Harold, Mariano, Vittoria, Mi, Huaiyu, Ninov, Momchil, Osumi-Sutherland, David, Pielot, Rainer, Smalla, Karl-Heinz, Tang, Haiming, Tashman, Katherine, Toonen, Ruud F G, Verpelli, Chiara, Reig-Viader, Rita, Watanabe, Kyoko, van Weering, Jan, Achsel, Tilmann, Ashrafi, Ghazaleh, Asi, Nimra, Brown, Tyler C, De Camilli, Pietro, Feuermann, Marc, Foulger, Rebecca E, Gaudet, Pascale, Joglekar, Anoushka, Kanellopoulos, Alexandros, Malenka, Robert, Nicoll, Roger A, Pulido, Camila, de Juan-Sanz, Jaime, Sheng, Morgan, Südhof, Thomas C, Tilgner, Hagen U, Bagni, Claudia, Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Dieterich, Daniela C, Gundelfinger, Eckart D, Hoogenraad, Casper, Huganir, Richard L, Jahn, Reinhard, Kaeser, Pascal S, Kim, Eunjoon, Kreutz, Michael R, McPherson, Peter S, Neale, Ben M, O'Connor, Vincent, Posthuma, Danielle, Ryan, Timothy A, Sala, Carlo, Feng, Guoping, Hyman, Steven E, Thomas, Paul D, Smit, August B, Verhage, Matthijs, Sub Cell Biology, Celbiologie, Koopmans, Frank, van Nierop, Pim, Andres-Alonso, Maria, Byrnes, Andrea, Cijsouw, Tony, Coba, Marcelo P, Cornelisse, L Niels, Farrell, Ryan J, Goldschmidt, Hana L, Howrigan, Daniel P, Hussain, Natasha K, Imig, Cordelia, de Jong, Arthur P H, Jung, Hwajin, Kohansalnodehi, Mahdokht, Kramarz, Barbara, Lipstein, Noa, Lovering, Ruth C, MacGillavry, Harold, Mariano, Vittoria, Mi, Huaiyu, Ninov, Momchil, Osumi-Sutherland, David, Pielot, Rainer, Smalla, Karl-Heinz, Tang, Haiming, Tashman, Katherine, Toonen, Ruud F G, Verpelli, Chiara, Reig-Viader, Rita, Watanabe, Kyoko, van Weering, Jan, Achsel, Tilmann, Ashrafi, Ghazaleh, Asi, Nimra, Brown, Tyler C, De Camilli, Pietro, Feuermann, Marc, Foulger, Rebecca E, Gaudet, Pascale, Joglekar, Anoushka, Kanellopoulos, Alexandros, Malenka, Robert, Nicoll, Roger A, Pulido, Camila, de Juan-Sanz, Jaime, Sheng, Morgan, Südhof, Thomas C, Tilgner, Hagen U, Bagni, Claudia, Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Dieterich, Daniela C, Gundelfinger, Eckart D, Hoogenraad, Casper, Huganir, Richard L, Jahn, Reinhard, Kaeser, Pascal S, Kim, Eunjoon, Kreutz, Michael R, McPherson, Peter S, Neale, Ben M, O'Connor, Vincent, Posthuma, Danielle, Ryan, Timothy A, Sala, Carlo, Feng, Guoping, Hyman, Steven E, Thomas, Paul D, Smit, August B, and Verhage, Matthijs

Published
2019

24. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse

Author

Koopmans, F., van Nierop, Pim, Andres-Alonso, M., Byrnes, Andrea, Cijsouw, Tony, Coba, Marcelo P., Cornelisse, L. Niels, Farrell, Ryan J., Goldschmidt, Hana L., Howrigan, Daniel P., Hussain, Natasha K., Imig, Cordelia, de Jong, Arthur P.H., Jung, Hwajin, Kohansalnodehi, Mahdokht, Kramarz, Barbara, Lipstein, Noa, Lovering, Ruth C., MacGillavry, Harold, Mariano, Vittoria, Mi, Huaiyu, Ninov, Momchil, Osumi-Sutherland, D., Pielot, Rainer, Smalla, Karl Heinz, Tang, Haiming, Tashman, Katherine, Toonen, Ruud F.G., Verpelli, Chiara, Reig-Viader, Rita, Watanabe, K., van Weering, Jan, Achsel, Tilmann, Ashrafi, Ghazaleh, Asi, N., Brown, Tyler C., De Camilli, Pietro, Feuermann, Marc, Foulger, Rebecca E., Gaudet, Pascale, Joglekar, Anoushka, Kanellopoulos, Alexandros, Malenka, Robert, Nicoll, Roger A., Pulido, Camila, de Juan-Sanz, J., Sheng, Morgan, Südhof, Thomas C., Tilgner, Hagen U., Bagni, Claudia, Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Dieterich, Daniela C., Gundelfinger, Eckart D., Hoogenraad, Casper, Huganir, Richard L., Jahn, Reinhard, Kaeser, Pascal S., Kim, Eunjoon, Kreutz, Michael R., McPherson, Peter S., Neale, B. M., O'Connor, Vincent, Posthuma, Danielle, Ryan, Timothy A., Sala, C., Feng, Guoping, Hyman, Steven E., Thomas, Paul D., Smit, August B., Verhage, Matthijs, Koopmans, F., van Nierop, Pim, Andres-Alonso, M., Byrnes, Andrea, Cijsouw, Tony, Coba, Marcelo P., Cornelisse, L. Niels, Farrell, Ryan J., Goldschmidt, Hana L., Howrigan, Daniel P., Hussain, Natasha K., Imig, Cordelia, de Jong, Arthur P.H., Jung, Hwajin, Kohansalnodehi, Mahdokht, Kramarz, Barbara, Lipstein, Noa, Lovering, Ruth C., MacGillavry, Harold, Mariano, Vittoria, Mi, Huaiyu, Ninov, Momchil, Osumi-Sutherland, D., Pielot, Rainer, Smalla, Karl Heinz, Tang, Haiming, Tashman, Katherine, Toonen, Ruud F.G., Verpelli, Chiara, Reig-Viader, Rita, Watanabe, K., van Weering, Jan, Achsel, Tilmann, Ashrafi, Ghazaleh, Asi, N., Brown, Tyler C., De Camilli, Pietro, Feuermann, Marc, Foulger, Rebecca E., Gaudet, Pascale, Joglekar, Anoushka, Kanellopoulos, Alexandros, Malenka, Robert, Nicoll, Roger A., Pulido, Camila, de Juan-Sanz, J., Sheng, Morgan, Südhof, Thomas C., Tilgner, Hagen U., Bagni, Claudia, Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Dieterich, Daniela C., Gundelfinger, Eckart D., Hoogenraad, Casper, Huganir, Richard L., Jahn, Reinhard, Kaeser, Pascal S., Kim, Eunjoon, Kreutz, Michael R., McPherson, Peter S., Neale, B. M., O'Connor, Vincent, Posthuma, Danielle, Ryan, Timothy A., Sala, C., Feng, Guoping, Hyman, Steven E., Thomas, Paul D., Smit, August B., and Verhage, Matthijs

Abstract

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders (“synaptopathies”). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org). The SynGO consortium presents a framework to annotate synaptic protein locations and functions and annotations for 1,112 synaptic genes based on published experimental evidence. SynGO reports exceptional features and disease associations for synaptic genes and provides an online data analysis platform.

Published
2019
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28. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse

Author

Koopmans, Frank, primary, van Nierop, Pim, additional, Andres-Alonso, Maria, additional, Byrnes, Andrea, additional, Cijsouw, Tony, additional, Coba, Marcelo P., additional, Cornelisse, L. Niels, additional, Farrell, Ryan J., additional, Goldschmidt, Hana L., additional, Howrigan, Daniel P., additional, Hussain, Natasha K., additional, Imig, Cordelia, additional, de Jong, Arthur P.H., additional, Jung, Hwajin, additional, Kohansalnodehi, Mahdokht, additional, Kramarz, Barbara, additional, Lipstein, Noa, additional, Lovering, Ruth C., additional, MacGillavry, Harold, additional, Mariano, Vittoria, additional, Mi, Huaiyu, additional, Ninov, Momchil, additional, Osumi-Sutherland, David, additional, Pielot, Rainer, additional, Smalla, Karl-Heinz, additional, Tang, Haiming, additional, Tashman, Katherine, additional, Toonen, Ruud F.G., additional, Verpelli, Chiara, additional, Reig-Viader, Rita, additional, Watanabe, Kyoko, additional, van Weering, Jan, additional, Achsel, Tilmann, additional, Ashrafi, Ghazaleh, additional, Asi, Nimra, additional, Brown, Tyler C., additional, De Camilli, Pietro, additional, Feuermann, Marc, additional, Foulger, Rebecca E., additional, Gaudet, Pascale, additional, Joglekar, Anoushka, additional, Kanellopoulos, Alexandros, additional, Malenka, Robert, additional, Nicoll, Roger A., additional, Pulido, Camila, additional, de Juan-Sanz, Jaime, additional, Sheng, Morgan, additional, Südhof, Thomas C., additional, Tilgner, Hagen U., additional, Bagni, Claudia, additional, Bayés, Àlex, additional, Biederer, Thomas, additional, Brose, Nils, additional, Chua, John Jia En, additional, Dieterich, Daniela C., additional, Gundelfinger, Eckart D., additional, Hoogenraad, Casper, additional, Huganir, Richard L., additional, Jahn, Reinhard, additional, Kaeser, Pascal S., additional, Kim, Eunjoon, additional, Kreutz, Michael R., additional, McPherson, Peter S., additional, Neale, Ben M., additional, O’Connor, Vincent, additional, Posthuma, Danielle, additional, Ryan, Timothy A., additional, Sala, Carlo, additional, Feng, Guoping, additional, Hyman, Steven E., additional, Thomas, Paul D., additional, Smit, August B., additional, and Verhage, Matthijs, additional

Published
2019
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29. A role for TASK2 channels in the human immunological synapse.

Author

Fernández‐Orth, Juncal, Rolfes, Leoni, Gola, Lukas, Bittner, Stefan, Andronic, Joseph, Sukhorukov, Vladimir L., Sisario, Dmitri, Landgraf, Peter, Dieterich, Daniela C., Cerina, Manuela, Smalla, Karl‐Heinz, Kähne, Thilo, Budde, Thomas, Kovac, Stjepana, Ruck, Tobias, Sauer, Markus, and Meuth, Sven G.

Subjects
SYNAPSES, MASS analysis (Spectrometry), CALCIUM ions, POTASSIUM antagonists, T cells, AUTOIMMUNITY, T cell receptors
Abstract

The immunological synapse is a transient junction that occurs when the plasma membrane of a T cell comes in close contact with an APC after recognizing a peptide from the antigen‐MHC. The interaction starts when CRAC channels embedded in the T cell membrane open, flowing calcium ions into the cell. To counterbalance the ion influx and subsequent depolarization, Kv1.3 and KCa3.1 channels are recruited to the immunological synapse, increasing the extracellular K+ concentration. These processes are crucial as they initiate gene expression that drives T cell activation and proliferation. The T cell‐specific function of the K2P channel family member TASK2 channels and their role in autoimmune processes remains unclear. Using mass spectrometry analysis together with epifluorescence and super‐resolution single‐molecule localization microscopy, we identified TASK2 channels as novel players recruited to the immunological synapse upon stimulation. TASK2 localizes at the immunological synapse, upon stimulation with CD3 antibodies, likely interacting with these molecules. Our findings suggest that, together with Kv1.3 and KCa3.1 channels, TASK2 channels contribute to the proper functioning of the immunological synapse, and represent an interesting treatment target for T cell‐mediated autoimmune disorders. [ABSTRACT FROM AUTHOR]

Published
2021
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30. Cell-type-specific metabolic labeling of nascent proteomes in vivo

Author

Alvarez-Castelao, Beatriz, primary, Schanzenbächer, Christoph T, additional, Hanus, Cyril, additional, Glock, Caspar, additional, tom Dieck, Susanne, additional, Dörrbaum, Aline R, additional, Bartnik, Ina, additional, Nassim-Assir, Belquis, additional, Ciirdaeva, Elena, additional, Mueller, Anke, additional, Dieterich, Daniela C, additional, Tirrell, David A, additional, Langer, Julian D, additional, and Schuman, Erin M, additional

Published
2017
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31. Cleavable biotin probes for labeling of biomolecules via azide?alkyne cycloaddition

Author

Szychowski, Janek, Mahdavi, Alborz, Hodas, Jennifer J.L., Bagert, John D., Ngo, John T., Landgraf, Peter, Dieterich, Daniela C., Schuman, Erin M., and Tirrell, David A.

Subjects
Azides -- Chemical properties, Azides -- Electric properties, Ring formation (Chemistry) -- Analysis, Chemistry
Abstract

The article presents five different cleavable biotin probes, which can be employed for the labeling of biomolecules via the azide-alkyne cycloaddition process. These probes are shown to be extremely suitable for numerous biomolecular labeling and proteomic studies.

Published
2010

35. 14-3-3 Proteins regulate K2P5.1 surface expression on T lymphocytes

Author

Fernández-Orth, Juncal, primary, Ehling, Petra, additional, Ruck, Tobias, additional, Pankratz, Susann, additional, Hofmann, Majella-Sophie, additional, Landgraf, Peter, additional, Dieterich, Daniela C., additional, Smalla, Karl-Heinz, additional, Kähne, Thilo, additional, Seebohm, Guiscard, additional, Budde, Thomas, additional, Wiendl, Heinz, additional, Bittner, Stefan, additional, and Meuth, Sven G., additional

Published
2016
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36. Proteome rearrangements after auditory learning: high‐resolution profiling of synapse‐enriched protein fractions from mouse brain

Author

Kähne, Thilo, primary, Richter, Sandra, additional, Kolodziej, Angela, additional, Smalla, Karl‐Heinz, additional, Pielot, Rainer, additional, Engler, Alexander, additional, Ohl, Frank W., additional, Dieterich, Daniela C., additional, Seidenbecher, Constanze, additional, Tischmeyer, Wolfgang, additional, Naumann, Michael, additional, and Gundelfinger, Eckart D., additional

Published
2016
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40. Cell-selective labelling of proteomes in Drosophila melanogaster

Author

Erdmann, Ines, primary, Marter, Kathrin, additional, Kobler, Oliver, additional, Niehues, Sven, additional, Abele, Julia, additional, Müller, Anke, additional, Bussmann, Julia, additional, Storkebaum, Erik, additional, Ziv, Tamar, additional, Thomas, Ulrich, additional, and Dieterich, Daniela C., additional

Published
2015
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43. 14-3-3 Proteins regulate K2P5.1 surface expression on T lymphocytes.

Author

Fernández‐Orth, Juncal, Ehling, Petra, Ruck, Tobias, Pankratz, Susann, Hofmann, Majella‐Sophie, Landgraf, Peter, Dieterich, Daniela C., Smalla, Karl‐Heinz, Kähne, Thilo, Seebohm, Guiscard, Budde, Thomas, Wiendl, Heinz, Bittner, Stefan, and Meuth, Sven G.

Subjects
MULTIPLE sclerosis, PROTEIN expression, T cells, AUTOIMMUNE diseases, PATHOLOGICAL physiology, PATIENTS
Abstract

K2P5.1 channels (also called TASK-2 or Kcnk5) have already been shown to be relevant in the pathophysiology of autoimmune disease because they are known to be upregulated on peripheral and central T lymphocytes of multiple sclerosis (MS) patients. Moreover, overexpression of K2P5.1 channels in vitro provokes enhanced T-cell effector functions. However, the molecular mechanisms regulating intracellular K2P5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K2P5.1 channels on T lymphocytes. Using mass spectrometry analysis, we have identified 14-3-3 proteins as novel binding partners of K2P5.1 channels. We show that a non-classical 14-3-3 consensus motif (R-X-X-pT/S-x) at the channel's C-terminus allows the binding between K2P5.1 and 14-3-3. The mutant K2P5.1/S266A diminishes the protein-protein interaction and reduces the amplitude of membrane currents. Application of a non-peptidic 14-3-3 inhibitor (BV02) significantly reduces the number of wild-type channels in the plasma membrane, whereas the drug has no effect on the trafficking of the mutated channel. Furthermore, blocker application reduces T-cell effector functions. Taken together, we demonstrate that 14-3-3 interacts with K2P5.1 and plays an important role in channel trafficking. [ABSTRACT FROM AUTHOR]

Published
2017
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48. QuaNCAT: quantitating proteome dynamics in primary cells

Author

Howden, Andrew J M, primary, Geoghegan, Vincent, additional, Katsch, Kristin, additional, Efstathiou, Georgios, additional, Bhushan, Bhaskar, additional, Boutureira, Omar, additional, Thomas, Benjamin, additional, Trudgian, David C, additional, Kessler, Benedikt M, additional, Dieterich, Daniela C, additional, Davis, Benjamin G, additional, and Acuto, Oreste, additional

Published
2013
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