Identification of evolutionarily conserved ...
Document type :
Article dans une revue scientifique: Article original
PMID :
Permalink :
Title :
Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
Author(s) :
Swarup, Vivek [Auteur]
Hinz, Flora I. [Auteur]
Rexach, Jessica E. [Auteur]
Noguchi, Ken-Ichi [Auteur]
Toyoshiba, Hiroyoshi [Auteur]
Oda, Akira [Auteur]
Hirai, Keisuke [Auteur]
Sarkar, Arjun [Auteur]
Seyfried, Nicholas T. [Auteur]
Cheng, Chialin [Auteur]
Haggarty, Stephen J. [Auteur]
Grossman, Murray [Auteur]
Van Deerlin, Vivianna M. [Auteur]
Trojanowski, John Q. [Auteur]
Lah, James J. [Auteur]
Levey, Allan I. [Auteur]
Kondou, Shinichi [Auteur]
Geschwind, Daniel H. [Auteur]
Hinz, Flora I. [Auteur]
Rexach, Jessica E. [Auteur]
Noguchi, Ken-Ichi [Auteur]
Toyoshiba, Hiroyoshi [Auteur]
Oda, Akira [Auteur]
Hirai, Keisuke [Auteur]
Sarkar, Arjun [Auteur]
Seyfried, Nicholas T. [Auteur]
Cheng, Chialin [Auteur]
Haggarty, Stephen J. [Auteur]
Grossman, Murray [Auteur]
Van Deerlin, Vivianna M. [Auteur]
Trojanowski, John Q. [Auteur]
Lah, James J. [Auteur]
Levey, Allan I. [Auteur]
Kondou, Shinichi [Auteur]
Geschwind, Daniel H. [Auteur]
Journal title :
Nature medicine
Abbreviated title :
Nat. Med.
Publication date :
2018-12-03
ISSN :
1546-170X
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
CHU Lille
CNRS
Inserm
Université de Lille
CNRS
Inserm
Université de Lille
Collections :
Research team(s) :
Troubles cognitifs dégénératifs et vasculaires
Submission date :
2019-11-27T14:29:30Z