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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 152-164 |
| Number of pages | 13 |
| Journal | Nature Medicine |
| Volume | 25 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. / International Frontotemporal Dementia Genomics Consortium.
In: Nature Medicine, Vol. 25, No. 1, 01.01.2019, p. 152-164.Research output: Contribution to journal › Article
TY - JOUR
T1 - Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
AU - International Frontotemporal Dementia Genomics Consortium
AU - Swarup, Vivek
AU - Hinz, Flora I.
AU - Rexach, Jessica E.
AU - Noguchi, Ken ichi
AU - Toyoshiba, Hiroyoshi
AU - Oda, Akira
AU - Hirai, Keisuke
AU - Sarkar, Arjun
AU - Seyfried, Nicholas T.
AU - Cheng, Chialin
AU - Haggarty, Stephen J.
AU - Ferrari, Raffaele
AU - Rohrer, Jonathan D.
AU - Ramasamy, Adaikalavan
AU - Hardy, John
AU - Hernandez, Dena G.
AU - Nalls, Michael A.
AU - Singleton, Andrew B.
AU - Kwok, John B.J.
AU - Dobson-Stone, Carol
AU - Brooks, William S.
AU - Schofield, Peter R.
AU - Halliday, Glenda M.
AU - Hodges, John R.
AU - Piguet, Olivier
AU - Bartley, Lauren
AU - Thompson, Elizabeth
AU - Haan, Eric
AU - Hernández, Isabel
AU - Ruiz, Agustín
AU - Boada, Mercè
AU - Borroni, Barbara
AU - Padovani, Alessandro
AU - Cairns, Nigel J.
AU - Cruchaga, Carlos
AU - Binetti, Giuliano
AU - Ghidoni, Roberta
AU - Benussi, Luisa
AU - Forloni, Gianluigi
AU - Albani, Diego
AU - Galimberti, Daniela
AU - Fenoglio, Chiara
AU - Serpente, Maria
AU - Scarpini, Elio
AU - Clarimón, Jordi
AU - Lleó, Alberto
AU - Blesa, Rafael
AU - Waldö, Maria Landqvist
AU - Nilsson, Karin
AU - Grafman, Jordan Henry
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058010718&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058010718&partnerID=8YFLogxK
U2 - 10.1038/s41591-018-0223-3
DO - 10.1038/s41591-018-0223-3
M3 - Article
VL - 25
SP - 152
EP - 164
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 1
ER -