Identification of evolutionarily conserved ...
Type de document :
Article dans une revue scientifique: Article original
PMID :
URL permanente :
Titre :
Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
Auteur(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]
Titre de la revue :
Nature medicine
Nom court de la revue :
Nat. Med.
Date de publication :
2018-12-03
ISSN :
1546-170X
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [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 ...
Lire la suite >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.Lire moins >
Lire la suite >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.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
CHU Lille
CNRS
Inserm
Université de Lille
CNRS
Inserm
Université de Lille
Collections :
Équipe(s) de recherche :
Troubles cognitifs dégénératifs et vasculaires
Date de dépôt :
2019-11-27T14:29:30Z