Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
Open accessAbstract
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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They identified a neurodegeneration-associated inflammatory module (NAI) and a synaptic (NAS) module that are also dysregulated in human FTD, AD, or ALS samples, but not in human major depressive disorder, schizophrenia, or bipolar disorder samples.
“They identified a neurodegeneration-associated inflammatory module (NAI) and a synaptic (NAS) module that are also dysregulated in human FTD, AD, or ALS samples, but not in human major depressive disorder, schizophrenia, or bipolar disorder samples.”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Swarup et al., 2019
Swarup et al. identified two major neurodegeneration-associated modules in FTD mouse models.
“Swarup et al. identified two major neurodegeneration-associated modules in FTD mouse models.”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Swarup et al., 2019
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- Authors
- Swarup, V., Hinz, F. I., Rexach, J. E., Noguchi, K.-I., Toyoshiba, H., Oda, A., Hirai, K., Sarkar, A., Seyfried, N. T., Cheng, C., Haggarty, S. J., International Frontotemporal Dementia Genomics Consortium, Ferrari, R., Rohrer, J. D., Ramasamy, A., Hardy, J., Hernandez, D. G., Nalls, M. A., Singleton, A. B., Kwok, J. B. J., Dobson-Stone, C., Brooks, W. S., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cairns, N. J., Cruchaga, C., Binetti, G., Ghidoni, R., Benussi, L., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Blesa, R., Waldö, M. L., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G.-Y. R., Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Thomas, A. J., Jaros, E., Pietrini, P., Huey, E. D., Wassermann, E. M., Tierney, M. C., Baborie, A., Pastor, P., Ortega-Cubero, S., Razquin, C., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., George-Hyslop, P. S., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Pickering-Brown, S., Momeni, P., van der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Brice, A., Hannequin, D., Golfier, V., Vercelletto, M., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Gasparoni, G., Pichler, S., Ibach, B., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Gerhard, A., Richardson, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Miller, B. L., Karydas, A. M., Rosen, H., Seeley, W. W., van Swieten, J. C., Dopper, E. G. P., Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H.-H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Ferrucci, L., Kapogiannis, D., Grossman, M., Van Deerlin, V. M., Trojanowski, J. Q., Lah, J. J., Levey, A. I., Kondou, S., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- Takeda (Japan) (JP)
- Emory University (US)
- Harvard University (US)
- University College London (GB)
- National Institutes of Health (US)
- Neuroscience Research Australia (AU)
- Women's and Children's Hospital (AU)
- Fundació ACE (ES)
- University of Brescia (IT)
- Washington University in St. Louis (US)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- Mario Negri Institute for Pharmacological Research (IT)
- University of Milan (IT)
- Universitat Autònoma de Barcelona (ES)
- Lund University (SE)
- University of British Columbia (CA)
- University of Manchester (GB)
- Northwestern University (US)
- Newcastle University (GB)
- IMT School for Advanced Studies Lucca (IT)
- Columbia University (US)
- National Institute of Neurological Disorders and Stroke (US)
- University of Alberta (CA)
- Centro de Investigación Médica Aplicada (ES)
- Imperial College London (GB)
- Technical University of Munich (DE)
- University of Turin (IT)
- University of Toronto (CA)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- University of Cambridge (GB)
- University of California San Diego (US)
- MRC Prion Unit (GB)
- Ludwig-Maximilians-Universität München (DE)
- Texas Tech University (US)
- Vita-Salute San Raffaele University (IT)
- Inserm (FR)
- Centre Hospitalier Universitaire de Rouen (FR)
- Centre Hospitalier de Saint-Brieuc (FR)
- Centre Hospitalier Universitaire de Nantes (FR)
- University of Florence (IT)
- Copenhagen University Hospital (DK)
- Universitätsklinikum des Saarlandes (DE)
- University of Regensburg (DE)
- UCL Queen Square Institute of Neurology (GB)
- German Center for Neurodegenerative Diseases (DE)
- Presidio Ospedaliero Lamezia Terme (IT)
- Mayo Clinic (US)
- University of California, San Francisco (US)
- Erasmus MC (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Bari Aldo Moro (IT)
- Agostino Gemelli University Polyclinic (IT)
- University of Salerno (IT)
- MultiMedica (IT)
- Federico II University Hospital (IT)
- Karolinska Institutet (SE)
- Université de Lille (FR)
- National Institute on Aging (US)
- Corresponding author
- Geschwind, Daniel H.
- ORCID
- Swarup, Vivek
- Rexach, Jessica E.
- Toyoshiba, Hiroyoshi
- Oda, Akira
- Hirai, Keisuke
- Sarkar, Arjun
- Seyfried, Nicholas T.
- Haggarty, Stephen J.
- Ferrari, Raffaele
- Rohrer, Jonathan D.
- Ramasamy, Adaikalavan
- Hardy, John
- Hernandez, Dena G.
- Singleton, Andrew B.
- Kwok, John B. J.
- Brooks, William S.
- Schofield, Peter R.
- Halliday, Glenda M.
- Hodges, John R.
- Piguet, Olivier
- Haan, Eric
- Hernández, Isabel
- Borroni, Barbara
- Padovani, Alessandro
- Cairns, Nigel J.
- Cruchaga, Carlos
- Binetti, Giuliano
- Ghidoni, Roberta
- Benussi, Luisa
- Forloni, Gianluigi
- Albani, Diego
- Galimberti, Daniela
- Fenoglio, Chiara
- Clarimón, Jordi
- Lleó, Alberto
- Blesa, Rafael
- Waldö, Maria Landqvist
- Nilsson, Karin
- Nilsson, Christer
- Mackenzie, Ian R. A.
- Hsiung, Ging-Yuek R.
- Mann, David M. A.
- Grafman, Jordan
- Morris, Christopher M.
- Attems, Johannes
- Griffiths, Timothy D.
- McKeith, Ian G.
- Thomas, Alan J.
- Pietrini, Pietro
- Huey, Edward D.
- Wassermann, Eric M.
- Perneczky, Robert
- Alexopoulos, Panagiotis
- Kurz, Alexander
- Rainero, Innocenzo
- Rubino, Elisa
- Pinessi, Lorenzo
- Rogaeva, Ekaterina
- Rossi, Giacomina
- Tagliavini, Fabrizio
- Giaccone, Giorgio
- Rowe, James B.
- Schlachetzki, Johannes C. M.
- Collinge, John
- Mead, Simon
- Danek, Adrian
- Pickering-Brown, Stuart
- Cruts, Marc
- Cappa, Stefano F.
- Brice, Alexis
- Hannequin, Didier
- Nacmias, Benedetta
- Sorbi, Sandro
- Bagnoli, Silvia
- Piaceri, Irene
- Nielsen, Jørgen E.
- Hjermind, Lena E.
- Rossor, Martin N.
- Fox, Nick C.
- Warren, Jason D.
- Spillantini, Maria Grazia
- Morris, Huw R.
- Rizzu, Patrizia
- Heutink, Peter
- Snowden, Julie S.
- Rollinson, Sara
- Gerhard, Alexander
- Richardson, Anna
- Bruni, Amalia C.
- Maletta, Raffaele
- Cupidi, Chiara
- Bernardi, Livia
- Anfossi, Maria
- Gallo, Maura
- Smirne, Nicoletta
- Rademakers, Rosa
- Baker, Matt
- Dickson, Dennis W.
- Petersen, Ronald C.
- Josephs, Keith A.
- Boeve, Bradley F.
- Parisi, Joseph E.
- Miller, Bruce L.
- Seeley, William W.
- Dopper, Elise G. P.
- Seelaar, Harro
- Pijnenburg, Yolande A. L.
- Scheltens, Philip
- Logroscino, Giancarlo
- Capozzo, Rosa
- Novelli, Valeria
- Puca, Annibale A.
- Franceschi, Massimo
- Milan, Graziella
- Graff, Caroline
- Pasquier, Florence
- Deramecourt, Vincent
- Lebouvier, Thibaud
- Ferrucci, Luigi
- Kapogiannis, Dimitrios
- Lah, James J.
- Levey, Allan I.
- Geschwind, Daniel H.
- Venue
- Nature Medicine
- Published
- 2018-12-03
- Volume
- 25
- Issue
- 1
- Pages
- 152-164
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6602064
- OpenAlex
- W2903507433
- Cited by
- 136
- References
- 79
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 14 · 2023: 20 · 2022: 26 · 2021: 24 · 2020: 20 · 2019: 9
- FWCI
- 9.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- DZNE Pub (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Larry L. Hillblom Foundation
- Eli Lilly and Company
- Emory University
- Mayo Foundation for Medical Education and Research (U24 NS072026, AG016574)
- Arizona Department of Health Services (P30 AG19610, P50 AG016574, U24 NS072026, 211002, R01 AG032990)
- CurePSP
- Wellcome Trust (203249/Z/16/Z)
- National Institute for Health and Care Research (NF-SI-0512-10033, NF-SI-0611-10048, NF-SI-0617-10175)
- National Institutes of Health (211002, AG016574, NS065723, AG046139, AG19610, AG017216, AG003949, AG025711)
- Medical Research Council (MR/J009482/1, MR/N012453/1, MC_G1000734)
- National Institute on Aging (211002, U01-AG006576, R01 AG003949, AG046139, R01AG018023, AG016574, AG-19610, U01AG006786, P01AG003949, AG-006786, P30AG010124, R01-AG025711, P01AG017586, P50AG025711, AG025711, P50AG005681, R01AG032990, P30AG019610, U01AG046161, P01AG003991, P01AG017216, U01AG046139, AG017216, AG003949, P01AG019724, R01-AG017216, P50AG016574)
- National Institute of Neurological Disorders and Stroke (R01NS080820, R25NS065723, NS072026, 211002, NS080820, U24NS072026, NS065723)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal dementia, neurodegeneration, gene co-expression modules, MAPT mutations, GRN mutations, miR-203, neuronal cell death, drug repurposing, small molecules
- MeSH terms
- Animals, Dementia, Disease Models, Animal, Gene Expression Regulation, Genetic Vectors, Humans, Mice, Inbred C57BL, Mice, Transgenic, RNA, Messenger, Reproducibility of Results, tau Proteins, Cell Death, Evolution, Molecular, Neurodegenerative Diseases, Genetic Predisposition to Disease, MicroRNAs, Proteomics, Gene Regulatory Networks, Frontotemporal Dementia, Transcriptome
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