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Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

2018; Nature Portfolio; Volume: 25; Issue: 1 Linguagem: Inglês

10.1038/s41591-018-0223-3

1546-170X

Vivek Swarup, Flora I. Hinz, Jessica E. Rexach, K Noguchi, Hiroyoshi Toyoshiba, Akira Oda, Keisuke Hirai, Arjun Sarkar, Nicholas T. Seyfried, Chialin Cheng, Stephen J. Haggarty, Raffaele Ferrari, Jonathan D. Rohrer, Adaikalavan Ramasamy, John Hardy, Dena Hernandez, Mike A. Nalls, Andrew B. Singleton, John B. Kwok, Carol Dobson‐Stone, William S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustı́n Ruiz, Merçé Boada, Barbara Borroni, Alessandro Padovani, Nigel J. Cairns, Carlos Cruchaga, Giuliano Binetti, Roberta Ghidoni, Luisa Benussi, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, María Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, María Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R. Mackenzie, Ging‐Yuek Robin Hsiung, David M. A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan Thomas, Evelyn Jaros, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Michael Tierney, Atik Baborie, Pau Pástor, Sara Ortega‐Cubero, Cristina Razquín, Elena Alonso, Robert Perneczky, Janine Diehl‐Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George‐Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B. Rowe, Johannes C. M. Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M. Van Deerlin, Murray Grossman, John Q. Trojanowski, Stuart Pickering‐Brown, Parastoo Momeni, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Leber, Alexis Brice, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E. Nielsen, Lena E. Hjermind, Markus J. Riemenschneider, Manuel Mayhaus, Gilles Gasparoni, Sabrina Pichler, Bernd Ibach, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Maria Grazia Spillantini, Huw R. Morris, Patrizia Rizzu, Peter Heutink, Julie S. Snowden, Sara Rollinson, Alexander Gerhard, Anna Richardson, Amalia C. Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W. Dickson, Neill R. Graff‐Radford, Ronald C. Petersen, David Knopman, Keith A. Josephs, Bradley F. Boeve, Joseph E. Parisi, Bruce L. Miller, Anna M. Karydas, Howard J. Rosen, William W. Seeley, John C. van Swieten, Elise G.P. Dopper, Harro Seelaar, Yolande A.L. Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale Alessandro Puca, M. Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei‐Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Thibaud Lebouvier, Luigi Ferrucci, Dimitrios Kapogiannis, Murray Grossman, Vivianna M. Van Deerlin, John Q. Trojanowski, James J. Lah, Allan I. Levey, Shinichi Kondou, Daniel H. Geschwind,

RNA Research and Splicing

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. Evolutionarily conserved gene modules mediate neurodegenerative dementia in a variety of mouse models and in postmortem brain tissue from patients.