Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Clinical and genetic characteristics of late-onset Huntington's disease

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Inflammatory markers of CHMP2B-mediated frontotemporal dementia

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

    Research output: Contribution to journalJournal articleResearchpeer-review

  • International Frontotemporal Dementia Genomics Consortium
  • 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
  • Murray Grossman
  • Vivianna M Van Deerlin
  • John Q Trojanowski
  • James J Lah
  • Allan I Levey
  • Shinichi Kondou
  • Daniel H Geschwind
  • Lena Elisabeth Hjermind (Member of study group)
  • Jørgen Erik Nielsen (Member of study group)
View graph of relations

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 languageEnglish
JournalNature Medicine
Volume25
Issue number1
Pages (from-to)152-164
Number of pages13
ISSN1078-8956
DOIs
Publication statusPublished - Jan 2019

ID: 56391356