Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Vivek Swarup, Flora I. Hinz, Jessica E. Rexach, Ken ichi 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 G. Hernandez, Michael A. Nalls, Andrew B. Singleton, John B.J. Kwok, Carol Dobson-StoneWilliam S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Nigel J. Cairns, Carlos Cruchaga, Giuliano Binetti, Roberta Ghidoni, Luisa Benussi, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R.A. Mackenzie, Ging Yuek R. Hsiung, David M.A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan J. Thomas, Evelyn Jaros, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Michael C. Tierney, Atik Baborie, Pau Pastor, Sara Ortega-Cubero, Cristina Razquin, 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

    Research output: Contribution to journalArticleResearch

    24 Citations (Scopus)

    Abstract

    © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.
    Original languageEnglish
    Pages (from-to)152-164
    JournalNature Medicine
    Volume25
    DOIs
    Publication statusPublished - 1 Jan 2019

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