Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

• Type of Material: Article
• Authors: Vivek Swarup, University of California, Los Angeles; Flora I. Hinz, University of California, Los Angeles; Jessica E. Rexach, University of California, Los Angeles; Ken-ichi Noguchi, Takeda Pharmaceutical Company Ltd.; Hiroyoshi Toyoshiba, Takeda Pharmaceutical Company Ltd.; Akira Oda, Takeda Pharmaceutical Company Ltd.; Keisuke Hirai, Takeda Pharmaceutical Company Ltd.; Arjun Sarkar, University of California, Los Angeles; Nicholas Seyfried, Emory University; Chialin Cheng, Massachusetts Institute of Technology; Stephen J. Haggarty, Massachusetts Institute of Technology; Murray Grossman, University of Pennsylvania; Vivianna M. Van Deerlin, University of Pennsylvania; John Q. Trojanowski, University of Pennsylvania; James J Lah, Emory University; Allan I Levey, Emory University
• Language: English
• Date: 2019-01-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41591-018-0223-3
• Title of Journal or Parent Work: Nature Medicine
• ISSN: 1078-8956
• Volume: 25
• Issue: 1
• Start Page: 152
• End Page: +
• Grant/Funding Information: Complete funding list available in full text.; Funding for this work was provided by Takeda Pharmaceuticals (D.H.G.; Rainwater Charitable Foundation/Tau consortium (D.H.G., S.J.H.); and NIH grants to D.H.G., S.J.H., A.L. (5U01AG046161), J.R. (5R25 NS065723); and Larry L. Hillblom Foundation Postdoctoral Fellowship to V.S.
• Keywords: Science & Technology; NEUROPATHOLOGY; LONG-TERM; FRONTOTEMPORAL DEMENTIA; COEXPRESSION; Life Sciences & Biomedicine; Medicine, Research & Experimental; TRANSCRIPTOME; Biochemistry & Molecular Biology; EXPRESSION ANALYSIS; COGNITIVE DEFICITS; TRANSGENIC MICE; Cell Biology; BRAIN; IMMUNE-RESPONSES; Research & Experimental Medicine
• Research Categories: Chemistry, Biochemistry; Biology, Genetics; Biology, Neuroscience

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.