Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

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 i...

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Autores: Swarup, V; Hinz, FI; Rexach, JE; Noguchi, K; Toyoshiba, H; Oda, A; Hirai, K; Sarkar, A; Seyfried, NT; Cheng, CL; Haggarty, SJ; Ferrari, R; Rohrer, JD; Ramasamy, A; Hardy, J; Hernandez, DG; Nalls, MA; Singleton, AB; Kwok, JBJ; Dobson-Stone, C; Brooks, WS; Schofield, PR; Halliday, GM; Hodges, JR; Piguet, O; Bartley, L; Thompson, E; Haan, E; Hernandez, I; Ruiz, A; Boada, M; Borroni, B; Padovani, A; Cairns, NJ; Cruchaga, C; Binetti, G; Ghidoni, R; Benussi, L; Forloni, G; Albani, D; Galimberti, D; Fenoglio, C; Serpente, M; Scarpini, E; Clarimon, J; Lleo, A; Blesa, R; Waldo, ML; Nilsson, K; Nilsson, C; Mackenzie, IRA; Hsiung, GYR; Mann, DMA; Grafman, J; Morris, CM; Attems, J; Griffiths, TD; McKeith, IG; Thomas, AJ; Jaros, E; Pietrini, P; Huey, ED; Wassermann, EM; Tierney, MC; Baborie, A; Pastor, P; Ortega-Cubero, S; Razquin, C; Alonso, E; Perneczky, R; Diehl-Schmid, J; Alexopoulos, P; Kurz, A; Rainero, I; Rubino, E; Pinessi, L; Rogaeva, E; St George-Hyslop, P; Rossi, G; Tagliavini, F; Giaccone, G; Rowe, JB; Schlachetzki, JCM; Uphill, J; Collinge, J; Mead, S; Danek, A; Pickering-Brown, S; Momeni, P; van der Zee, J; Cruts, M; Van Broeckhoven, C; Cappa, SF; Leber, I; Brice, A; Hannequin, D; Golfier, V; Vercelletto, M; Nacmias, B; Sorbi, S; Bagnoli, S; Piaceri, I; Nielsen, JE; Hjermind, LE; Riemenschneider, M; Mayhaus, M; Gasparoni, G; Pichler, S; Ibach, B; Rossor, MN; Fox, NC; Warren, JD; Spillantini, MG; Morris, HR; Rizzu, P; Heutink, P; Snowden, JS; Rollinson, S; Gerhard, A; Richardson, A; Bruni, AC; Maletta, R; Frangipane, F; Cupidi, C; Bernardi, L; Anfossi, M; Gallo, M; Conidi, ME; Smirne, N; Rademakers, R; Baker, M; Dickson, DW; Graff-Radford, NR; Petersen, RC; Knopman, D; Josephs, KA; Boeve, BF; Parisi, JE; Miller, BL; Karydas, AM; Rosen, H; Seeley, WW; van Swieten, JC; Dopper, EGP; Seelaar, H; Pijnenburg, YAL; Scheltens, P; Logroscino, G; Capozzo, R; Novelli, V; Puca, AA; Franceschi, M; Postiglione, A; Milan, G; Sorrentino, P; Kristiansen, M; Chiang, HH; Graff, C; Pasquier, F; Rollin, A; Deramecourt, V; Lebouvier, T; Ferrucci, L; Kapogiannis, D; Grossman, M; Van Deerlin, VM; Trojanowski, JQ; Lah, JJ; Levey, AI; Kondou, S; Geschwind, DH
Tipo de documento: Artículo
Estado:Published version
Fecha de publicación:2019
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p3143
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=3143
https://europepmc.org/articles/pmc6602064
Nivel de acceso:Acceso abierto
Sumario: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.

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