Summary: Researchers have identified two major groups of genes involved in mutations that result in an overproduction of tau. The findings could offer new avenues for treatments to slow the progression of dementia.
A UCLA-led research team has identified genetic processes involved in the neurodegeneration that occurs in dementia — an important step on the path toward developing therapies that could slow or halt the course of the disease. The findings appear Dec. 3 in the journal Nature Medicine.
The researchers discovered two major groups of genes involved in mutations that result in an overproduction of a protein called tau, a hallmark of the progressive loss of neurons seen in major forms of dementia. The study was largely done in mouse models of dementia, although the researchers performed additional experiments that indicated the same genetic process occurs in human brains.
Armed with that knowledge, the team searched a large database of the genetic effects of experimental drugs to identify those that might alter this loss of neurons, or neurodegeneration. In human cell cultures, the researchers showed that the use of these molecules interfered with neurodegeneration.
“Our study is the most comprehensive published effort to date to identify the source of neurodegeneration across species and provides an important roadmap for the development of potentially effective new drugs for Alzheimer’s disease and other dementia,” said senior author Dr. Daniel Geschwind, a professor of neurology and psychiatry who holds the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics at the David Geffen School of Medicine at UCLA.
More than 5 million people in the United States have Alzheimer’s disease or related dementias; that number is projected to nearly triple by 2060, according to the U.S. Centers for Disease Control and Prevention. There is currently no treatment that can alter the course of neurodegeneration-associated dementia.
Although scientists have identified genes associated with dementia risk, there is little understanding of how those genes contribute to the cascade of events that lead brain cells to die.
The research team sought to solve that puzzle through an approach known as “systems biology,” which applies powerful genomic and analytic tools to studying the genome holistically, taking into account the complex interactions of the thousands of genes and the cells and proteins they produce.
The researchers used systems biology to identify genetic processes in a mutation that results in the overproduction of tau in frontotemporal dementia, a form of early-onset dementia. A similar process also has been shown to play an important role in Alzheimer’s disease and another form of dementia known as supranuclear palsy, which affects both movement and cognition.
Geschwind’s team hypothesized that a reason why research with mouse models of dementia often fails to produce results translatable to humans is that most mouse studies have relied on a single inbred strain.
To increase the likelihood that their findings would have broader implications, the researchers studied the mutation caused by frontotemporal dementia in three genetically distinct strains of mice. The team looked at the genetic activity occurring in different parts of and points of time in a degenerating brain.
In the study, two gene clusters were found to be associated with neurodegeneration across all three mouse models and in the susceptible regions of the brain.
“There is still a significant amount of work that needs to be done to develop drugs that could be effectively used in humans against these targets, but this is an encouraging step,” said Geschwind, who also serves as co-director of the Center for Neurobehavioral Genetics at the Semel Institute for Neuroscience and Human Behavior at UCLA, and senior associate dean and associate vice chancellor of precision medicine at UCLA Health.
Other authors of the study are Vivek Swarup (first author), Flora Hinz, Jessica Rexach and Arjun Sarkar of UCLA; Ken-ichi Noguchi, Hiroyoshi Toyoshiba, Akira Oda, Keisuke Hirai and Shinichi Kondou of Takeda Pharmaceutical Co. Ltd. in Japan; Nicholas Seyfried, James Lah and Allan Levey of Emory University School of Medicine; Chialin Cheng and Stephen Haggarty of Harvard Medical School; and Murray Grossman, Vivianna Van Deerlin and John Trojanowski of the Perelman School of Medicine at the University of Pennsylvania.
Funding: Funding for the research came from Takeda Pharmaceuticals, the Rainwater Charitable Foundation, National Institutes of Health grants and Larry L. Hillblom Foundation fellowship grants.
Source: Elaine Schmidt – UCLA
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Original Research: Abstract for “Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia” by Vivek Swarup, Flora I. Hinz, Jessica E. Rexach, Ken-ichi Noguchi, Hiroyoshi Toyoshiba, Akira Oda, Keisuke Hirai, Arjun Sarkar, Nicholas T. Seyfried, Chialin Cheng, Stephen J. Haggarty, Raffaele Ferrari, Jonathan D. Rohrer, Adaikalavan Ramasamy, John Hardy, Dena G. Hernandez, Michael A. Nalls, Andrew B. Singleton, John B. J. Kwok, Carol Dobson-Stone, William S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Nigel J. Cairns, Carlos Cruchaga, Giuliano Binetti, Roberta Ghidoni, Luisa Benussi, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R. A. Mackenzie, Ging-Yuek R. Hsiung, David M. A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan J. Thomas, Evelyn Jaros, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Michael C. Tierney, Atik Baborie, Pau Pastor, Sara Ortega-Cubero, Cristina Razquin, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St. George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James B. Rowe, Johannes C. M. Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna M. Van Deerlin, Murray Grossman, John Q. Trojanowski, Stuart Pickering-Brown, Parastoo Momeni, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Leber, Alexis Brice, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E. Nielsen, Lena E. Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Gilles Gasparoni, Sabrina Pichler, Bernd Ibach, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Maria Grazia Spillantini, Huw R. Morris, Patrizia Rizzu, Peter Heutink, Julie S. Snowden, Sara Rollinson, Alexander Gerhard, Anna Richardson, Amalia C. Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Elena Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, David Knopman, Keith A. Josephs, Bradley F. Boeve, Joseph E. Parisi, Bruce L. Miller, Anna M. Karydas, Howard Rosen, William W. Seeley, John C. van Swieten, Elise G. P. Dopper, Harro Seelaar, Yolande A. L. Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale A. Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Thibaud Lebouvier, Luigi Ferrucci, Dimitrios Kapogiannis, Murray Grossman, Vivianna M. Van Deerlin, John Q. Trojanowski, James J. Lah, Allan I. Levey, Shinichi Kondou & Daniel H. Geschwind in Nature Medicine. Published December 3 2018.
Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
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.