Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
Vivek Swarup, Flora I Hinz, Jessica E Rexach, Ken-Ichi Noguchi, Hiroyoshi Toyoshiba, Akira Oda, Keisuke Hirai, Arjun Sarkar, Nicholas T Seyfried, Chialin Cheng, Stephen J Haggarty, International Frontotemporal Dementia Genomics Consortium; Murray Grossman, Vivianna M Van Deerlin, John Q Trojanowski, James J Lah, Allan I Levey, Shinichi Kondou, Daniel H Geschwind
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.
CITA DEL ARTÍCULO Nat Med. 2019 Jan;25(1):152-164. doi: 10.1038/s41591-018-0223-3. Epub 2018 Dec 3