1. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
- Author
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Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlos, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexis, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Gasparoni, Gilles, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrios, Lah, James J., Levey, Allan I., Kondou, Shinichi, Geschwind, Daniel H., Int Frontotemporal Dementia Gen, Swarup, Vivek, Hinz, Flora I., Rexach, Jessica E., Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T., Cheng, Chialin, Haggarty, Stephen J., Ferrari, Raffaele, Rohrer, Jonathan D., Ramasamy, Adaikalavan, Hardy, John, Hernandez, Dena G., Nalls, Michael A., Singleton, Andrew B., Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cairns, Nigel J., Cruchaga, Carlo, Binetti, Giuliano, Ghidoni, Roberta, Benussi, Luisa, Forloni, Gianluigi, Albani, Diego, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johanne, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Jaros, Evelyn, Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Tierney, Michael C., Baborie, Atik, Pastor, Pau, Ortega-Cubero, Sara, Razquin, Cristina, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagioti, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, George-Hyslop, Peter St., Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, Jame, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., Pickering-Brown, Stuart, Momeni, Parastoo, van der Zee, Julie, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Leber, Isabelle, Brice, Alexi, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthia, Mayhaus, Manuel, Gasparoni, Gille, Pichler, Sabrina, Ibach, Bernd, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Gerhard, Alexander, Richardson, Anna, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, Seeley, William W., van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebouvier, Thibaud, Ferrucci, Luigi, Kapogiannis, Dimitrio, Lah, James J., Levey, Allan I., Kondou, Shinichi, and Geschwind, Daniel H.
- Subjects
Proteomics ,Genetics and Molecular Biology (all) ,0301 basic medicine ,Messenger ,Gene regulatory network ,Inbred C57BL ,Biochemistry ,Transgenic ,Mice ,0302 clinical medicine ,Gene Regulatory Networks ,Regulation of gene expression ,Cell Death ,Drug discovery ,Neurodegeneration ,Neurodegenerative Diseases ,General Medicine ,Chemistry ,Frontotemporal Dementia ,030220 oncology & carcinogenesis ,Frontotemporal dementia ,Evolution ,Systems biology ,Genetic Vectors ,Animals ,Dementia ,Disease Models, Animal ,Gene Expression Regulation ,Genetic Predisposition to Disease ,Humans ,Mice, Inbred C57BL ,Mice, Transgenic ,MicroRNAs ,RNA, Messenger ,Reproducibility of Results ,Transcriptome ,tau Proteins ,Evolution, Molecular ,Computational biology ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,microRNA ,medicine ,Biochemistry, Genetics and Molecular Biology (all) ,Animal ,Molecular ,medicine.disease ,030104 developmental biology ,Disease Models ,RNA ,Human medicine - Abstract
Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.
- Published
- 2018