Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

International Frontotemporal Dementia Genomics Consortium; Raffaele Ferrari; Jonathan D. Rohrer; Adaikalavan Ramasamy; Jørgen Erik Nielsen; Lena E Hjermind; Thibaud Lebouvier; Luigi Ferrucci; Dimitrios Kapogiannis

doi:10.1038/s41591-018-0223-3

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

International Frontotemporal Dementia Genomics Consortium, Raffaele Ferrari, Jonathan D. Rohrer, Adaikalavan Ramasamy, Jørgen Erik Nielsen, Lena E Hjermind, Thibaud Lebouvier, Luigi Ferrucci, Dimitrios Kapogiannis

Department of Clinical Medicine

29 Citations (Scopus)

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.

Original language	English
Journal	Nature Medicine
Volume	25
Pages (from-to)	152-164
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-018-0223-3
Publication status	Published - 1 Jan 2019

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41591-018-0223-3

Cite this

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title = "Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia",

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.",

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author = "Vivek Swarup and Hinz, {Flora I} and Rexach, {Jessica E} and Ken-Ichi Noguchi and Hiroyoshi Toyoshiba and Akira Oda and Keisuke Hirai and Arjun Sarkar and Seyfried, {Nicholas T} and Chialin Cheng and Haggarty, {Stephen J} and {International Frontotemporal Dementia Genomics Consortium} and Murray Grossman and {Van Deerlin}, {Vivianna M} and Trojanowski, {John Q} and Lah, {James J} and Levey, {Allan I} and Shinichi Kondou and Geschwind, {Daniel H} and Raffaele Ferrari and Rohrer, {Jonathan D.} and Adaikalavan Ramasamy and Nielsen, {J{\o}rgen Erik} and Hjermind, {Lena E} and Thibaud Lebouvier and Luigi Ferrucci and Dimitrios Kapogiannis",

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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

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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

SN - 1078-8956

VL - 25

SP - 152

EP - 164

JO - Nature Medicine

JF - Nature Medicine

ER -

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Abstract

Keywords

UN SDGs

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