Swarup, Vivek and Hinz, Flora I. and Rexach, Jessica E. and Noguchi, Ken-ichi and Toyoshiba, Hiroyoshi and Oda, Akira and Hirai, Keisuke and Sarkar, Arjun and Seyfried, Nicholas T. and Cheng, Chialin and Haggarty, Stephen J. and Ferrari, Raffaele and Rohrer, Jonathan D. and Ramasamy, Adaikalavan and Hardy, John and Hernandez, Dena G. and Nalls, Michael A. and Singleton, Andrew B. and Kwok, John B. J. and Dobson-Stone, Carol and Brooks, William S. and Schofield, Peter R. and Halliday, Glenda M. and Hodges, John R. and Piguet, Olivier and Bartley, Lauren and Thompson, Elizabeth and Haan, Eric and Hernandez, Isabel and Ruiz, Agustin and Boada, Merce and Borroni, Barbara and Padovani, Alessandro and Cairns, Nigel J. and Cruchaga, Carlos and Binetti, Giuliano and Ghidoni, Roberta and Benussi, Luisa and Forloni, Gianluigi and Albani, Diego and Galimberti, Daniela and Fenoglio, Chiara and Serpente, Maria and Scarpini, Elio and Clarimon, Jordi and Lleo, Alberto and Blesa, Rafael and Waldo, Maria Landqvist and Nilsson, Karin and Nilsson, Christer and Mackenzie, Ian R. A. and Hsiung, Ging-Yuek R. and Mann, David M. A. and Grafman, Jordan and Morris, Christopher M. and Attems, Johannes and Griffiths, Timothy D. and McKeith, Ian G. and Thomas, Alan J. and Jaros, Evelyn and Pietrini, Pietro and Huey, Edward D. and Wassermann, Eric M. and Tierney, Michael C. and Baborie, Atik and Pastor, Pau and Ortega-Cubero, Sara and Razquin, Cristina and Alonso, Elena and Perneczky, Robert and Diehl-Schmid, Janine and Alexopoulos, Panagiotis and Kurz, Alexander and Rainero, Innocenzo and Rubino, Elisa and Pinessi, Lorenzo and Rogaeva, Ekaterina and St George-Hyslop, Peter and Rossi, Giacomina and Tagliavini, Fabrizio and Giaccone, Giorgio and Rowe, James B. and Schlachetzki, Johannes C. M. and Uphill, James and Collinge, John and Mead, Simon and Danek, Adrian and Van Deerlin, Vivianna M. and Grossman, Murray and Trojanowski, John Q. and Pickering-Brown, Stuart and Momeni, Parastoo and van der Zee, Julie and Cruts, Marc and Van Broeckhoven, Christine and Cappa, Stefano F. and Leber, Isabelle and Brice, Alexis and Hannequin, Didier and Golfier, Veronique and Vercelletto, Martine and Nacmias, Benedetta and Sorbi, Sandro and Bagnoli, Silvia and Piaceri, Irene and Nielsen, Jorgen E. and Hjermind, Lena E. and Riemenschneider, Matthias and Mayhaus, Manuel and Gasparoni, Gilles and Pichler, Sabrina and Ibach, Bernd and Rossor, Martin N. and Fox, Nick C. and Warren, Jason D. and Spillantini, Maria Grazia and Morris, Huw R. and Rizzu, Patrizia and Heutink, Peter and Snowden, Julie S. and Rollinson, Sara and Gerhard, Alexander and Richardson, Anna and Bruni, Amalia C. and Maletta, Raffaele and Frangipane, Francesca and Cupidi, Chiara and Bernardi, Livia and Anfossi, Maria and Gallo, Maura and Conidi, Maria Elena and Smirne, Nicoletta and Rademakers, Rosa and Baker, Matt and Dickson, Dennis W. and Graff-Radford, Neill R. and Petersen, Ronald C. and Knopman, David and Josephs, Keith A. and Boeve, Bradley F. and Parisi, Joseph E. and Miller, Bruce L. and Karydas, Anna M. and Rosen, Howard and Seeley, William W. and van Swieten, John C. and Dopper, Elise G. P. and Seelaar, Harro and Pijnenburg, Yolande A. L. and Scheltens, Philip and Logroscino, Giancarlo and Capozzo, Rosa and Novelli, Valeria and Puca, Annibale A. and Franceschi, Massimo and Postiglione, Alfredo and Milan, Graziella and Sorrentino, Paolo and Kristiansen, Mark and Chiang, Huei-Hsin and Graff, Caroline and Pasquier, Florence and Rollin, Adeline and Deramecourt, Vincent and Lebouvier, Thibaud and Ferrucci, Luigi and Kapogiannis, Dimitrios and Grossman, Murray and Van Deerlin, Vivianna M. and Trojanowski, John Q. and Lah, James J. and Levey, Allan I. and Kondou, Shinichi and Geschwind, Daniel H. (2019) Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. NATURE MEDICINE, 25 (1). 152-+. ISSN 1078-8956, 1546-170X
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FRONTOTEMPORAL DEMENTIA; EXPRESSION ANALYSIS; COGNITIVE DEFICITS; IMMUNE-RESPONSES; TRANSGENIC MICE; LONG-TERM; BRAIN; TRANSCRIPTOME; NEUROPATHOLOGY; COEXPRESSION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Apr 2020 07:57 |
| Last Modified: | 22 Apr 2020 07:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27928 |
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