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Nat Med. 2019 Jan;25(1):152-164. doi: 10.1038/s41591-018-0223-3. Epub 2018 Dec 3.

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia.

Collaborators (156)

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, Hernández 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, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, 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, George-Hyslop PS, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, 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.

Author information

1
Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
2
CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
3
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
4
Alzheimer's Disease Research Center and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
5
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
6
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
7
The Penn FTD Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
8
Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
9
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
10
Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.

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.

PMID:
30510257
DOI:
10.1038/s41591-018-0223-3

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