TY - JOUR
T1 - Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
AU - International Frontotemporal Dementia Genomics Consortium
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 - Ferrari, Raffaele
AU - Rohrer, Jonathan D.
AU - Ramasamy, Adaikalavan
AU - Hardy, John
AU - Hernandez, Dena G.
AU - Nalls, Michael A.
AU - Singleton, Andrew B.
AU - Kwok, John B.J.
AU - Dobson-Stone, Carol
AU - Brooks, William S.
AU - Schofield, Peter R.
AU - Halliday, Glenda M.
AU - Hodges, John R.
AU - Piguet, Olivier
AU - Bartley, Lauren
AU - Thompson, Elizabeth
AU - Haan, Eric
AU - Hernández, Isabel
AU - Ruiz, Agustín
AU - Boada, Mercè
AU - Borroni, Barbara
AU - Padovani, Alessandro
AU - Cairns, Nigel J.
AU - Cruchaga, Carlos
AU - Binetti, Giuliano
AU - Ghidoni, Roberta
AU - Benussi, Luisa
AU - Forloni, Gianluigi
AU - Albani, Diego
AU - Galimberti, Daniela
AU - Fenoglio, Chiara
AU - Serpente, Maria
AU - Scarpini, Elio
AU - Clarimón, Jordi
AU - Lleó, Alberto
AU - Blesa, Rafael
AU - Waldö, Maria Landqvist
AU - Nilsson, Karin
AU - Grafman, Jordan
N1 - Funding Information:
Funding for this work was provided by Takeda Pharmaceuticals (D.H.G.), Rainwater Charitable Foundation/Tau consortium (D.H.G., S.J.H.), NIH grants to D.H.G., S.J.H., A.L. (5U01AG046161) and J.R. (5R25 NS065723) and Larry L. Hillblom Foundation Postdoctoral Fellowship to V.S. K.N., H.T., A.O., K.H. and S.K. are employees of Takeda Pharmaceuticals. The authors thank M. Hattori, Y. Obayashi and K. Nakamura for their contribution to the TPR50 mouse sample preparation and analysis. The authors thank M. Gearing at the Emory Alzheimer’s Disease Research Center brain bank for providing human FTD samples. The authors also thank N. Parikshak for help with network analysis and critical reading of the manuscript. We thank Eli Lilly and Company scientists for generating the Tg4510 microglia RNA-seq data and providing access to them. For the PSP and FTD temporal cortex RNA-seq dataset, study data were provided by the following sources: Mayo Clinic Alzheimer’s Disease Genetic Studies, led by N. Taner and S. G. Younkin, Mayo Clinic Jacksonville, using samples from the Mayo Clinic Study of Aging, Mayo Clinic Alzheimer’s Disease Research Center, and Mayo Clinic Brain Bank. Data collection was supported through funding by National Institute on Aging (NIA) grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the NIA (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. Tg4510 replication and CRND8 RNA-seq data were provided by the NIH U01 AG046139. We thank J. Lewis, K. Duff, D. Westaway and D. Borchelt for generating these lines of transgenic mice and providing access to them.
Funding Information:
D.H.G. has received research funding from Takeda Pharmaceutical Company Limited. K.N., H.T., A.O., K.H. and S.K. are employees of Takeda Pharmaceutical Company Limited.
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/1/1
Y1 - 2019/1/1
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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85058010718&partnerID=8YFLogxK
U2 - 10.1038/s41591-018-0223-3
DO - 10.1038/s41591-018-0223-3
M3 - Article
C2 - 30510257
AN - SCOPUS:85058010718
VL - 25
SP - 152
EP - 164
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 1
ER -