TY - JOUR

T1 - Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

AU - Swarup, Vivek

AU - Hinz, Flora I

AU - Rexach, Jessica E

AU - Noguchi, Ken-Ichi

AU - Toyoshiba, Hiroyoshi

AU - Oda, Akira

AU - Hirai, Keisuke

AU - Sarkar, Arjun

AU - Seyfried, Nicholas T

AU - Cheng, Chialin

AU - Haggarty, Stephen J

AU - International Frontotemporal Dementia Genomics Consortium

AU - Grossman, Murray

AU - Van Deerlin, Vivianna M

AU - Trojanowski, John Q

AU - Lah, James J

AU - Levey, Allan I

AU - Kondou, Shinichi

AU - Geschwind, Daniel H

AU - Ferrari, Raffaele

AU - Rohrer, Jonathan D.

AU - Ramasamy, Adaikalavan

AU - Nielsen, Jørgen Erik

AU - Hjermind, Lena E

AU - Lebouvier, Thibaud

AU - Ferrucci, Luigi

AU - Kapogiannis, Dimitrios

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Death/genetics

KW - Dementia/genetics

KW - Disease Models, Animal

KW - Evolution, Molecular

KW - Frontotemporal Dementia/genetics

KW - Gene Expression Regulation

KW - Gene Regulatory Networks

KW - Genetic Predisposition to Disease

KW - Genetic Vectors/metabolism

KW - Humans

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - MicroRNAs/genetics

KW - Neurodegenerative Diseases/genetics

KW - Proteomics

KW - RNA, Messenger/genetics

KW - Reproducibility of Results

KW - Transcriptome/genetics

KW - tau Proteins/metabolism

U2 - 10.1038/s41591-018-0223-3

DO - 10.1038/s41591-018-0223-3

M3 - Journal article

C2 - 30510257

VL - 25

SP - 152

EP - 164

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

ER -