1. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
- Author
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Swarup, Vivek, Hinz, Flora I, Rexach, Jessica E, Noguchi, Ken-Ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T, Cheng, Chialin, Haggarty, Stephen J, International Frontotemporal Dementia Genomics Consortium, Grossman, Murray, Van Deerlin, Vivianna M, Trojanowski, John Q, Lah, James J, Levey, Allan I, Kondou, Shinichi, and Geschwind, Daniel H
- Subjects
Proteomics ,Aging ,Evolution ,Messenger ,Genetic Vectors ,Immunology ,tau Proteins ,Neurodegenerative ,Inbred C57BL ,Alzheimer's Disease ,Medical and Health Sciences ,Transgenic ,Mice ,Rare Diseases ,Acquired Cognitive Impairment ,Genetics ,Animals ,Humans ,2.1 Biological and endogenous factors ,Genetic Predisposition to Disease ,Gene Regulatory Networks ,Aetiology ,International Frontotemporal Dementia Genomics Consortium ,Cell Death ,Animal ,Human Genome ,Neurosciences ,Reproducibility of Results ,Molecular ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative Diseases ,Brain Disorders ,MicroRNAs ,Frontotemporal Dementia (FTD) ,Orphan Drug ,Gene Expression Regulation ,Frontotemporal Dementia ,Disease Models ,Neurological ,RNA ,Dementia ,Transcriptome ,Biotechnology - 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.
- Published
- 2019