Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / genetics
  • Dementia / genetics*
  • Disease Models, Animal
  • Evolution, Molecular*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / pathology
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Genetic Predisposition to Disease
  • Genetic Vectors / metabolism
  • Humans
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Neurodegenerative Diseases / genetics*
  • Proteomics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Transcriptome / genetics
  • tau Proteins / metabolism

Substances

  • MicroRNAs
  • RNA, Messenger
  • tau Proteins