TY - JOUR
T1 - Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
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 - International Frontotemporal Dementia Genomics Consortium
AU - Grossman, Murray
AU - Van Deerlin, Vivianna M
AU - Trojanowski, John Q
AU - Lah, James J
AU - Levey, Allan I
AU - Kondou, Shinichi
AU - Geschwind, Daniel H
AU - Ferrari, Raffaele
AU - Rohrer, Jonathan D.
AU - Ramasamy, Adaikalavan
AU - Nielsen, Jørgen Erik
AU - Hjermind, Lena E
AU - Lebouvier, Thibaud
AU - Ferrucci, Luigi
AU - Kapogiannis, Dimitrios
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.
KW - Animals
KW - Cell Death/genetics
KW - Dementia/genetics
KW - Disease Models, Animal
KW - Evolution, Molecular
KW - Frontotemporal Dementia/genetics
KW - Gene Expression Regulation
KW - Gene Regulatory Networks
KW - Genetic Predisposition to Disease
KW - Genetic Vectors/metabolism
KW - Humans
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - MicroRNAs/genetics
KW - Neurodegenerative Diseases/genetics
KW - Proteomics
KW - RNA, Messenger/genetics
KW - Reproducibility of Results
KW - Transcriptome/genetics
KW - tau Proteins/metabolism
U2 - 10.1038/s41591-018-0223-3
DO - 10.1038/s41591-018-0223-3
M3 - Journal article
C2 - 30510257
SN - 1078-8956
VL - 25
SP - 152
EP - 164
JO - Nature Medicine
JF - Nature Medicine
ER -
