Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
Research output: Contribution to journal › Journal article › Research › peer-review
International Frontotemporal Dementia Genomics Consortium, Raffaele Ferrari, Jonathan D. Rohrer, Adaikalavan Ramasamy, Jørgen Erik Nielsen, Lena E Hjermind, Thibaud Lebouvier, Luigi Ferrucci, Dimitrios Kapogiannis
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.
|Publication status||Published - 2019|
- Animals, Cell Death/genetics, Dementia/genetics, Disease Models, Animal, Evolution, Molecular, Frontotemporal Dementia/genetics, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genetic Vectors/metabolism, Humans, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs/genetics, Neurodegenerative Diseases/genetics, Proteomics, RNA, Messenger/genetics, Reproducibility of Results, Transcriptome/genetics, tau Proteins/metabolism