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CXCR4 involvement in neurodegenerative diseases

2018; Springer Nature; Volume: 8; Issue: 1 Linguagem: Inglês

10.1038/s41398-017-0049-7

2158-3188

Luke W. Bonham, Celeste M. Karch, Chun Chieh Fan, Chin Hong Tan, Ethan G. Geier, Yunpeng Wang, Natalie Wen, Iris Broce, Yi Li, Matthew J. Barkovich, Raffaele Ferrari, John Hardy, Parastoo Momeni, Günter U. Höglinger, Ulrich Müller, Christopher P. Hess, Leo P. Sugrue, William P. Dillon, Gerard D. Schellenberg, Bruce L. Miller, Ole A. Andreassen, Anders M. Dale, A. James Barkovich, Jennifer S. Yokoyama, Rahul S. Desikan, Raffaele Ferrari, D. G. Hernandez, Mike A. Nalls, Jonathan D. Rohrer, Adaikalavan Ramasamy, John B. Kwok, Carol Dobson‐Stone, Peter R. Schofield, Glenda M. Halliday, J. R. Hodges, Olivier Piguet, Lauren Bartley, E. Aubrey Thompson, Eric Haan, Ivó H. Hernández, Agustı́n Ruiz, Merçé Boada, Barbara Borroni, Alessandro Padovani, Carlos Cruchaga, N.J. Cairns, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, María Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, María Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R. Mackenzie, Ging‐Yuek Robin Hsiung, David Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griffiths, Ian G. McKeith, Alan Thomas, Pietro Pietrini, Edward D. Huey, Eric M. Wassermann, Atik Baborie, Evelyn Jaros, Michael Tierney, Pau Pástor, Cristina Razquín, Sara Ortega‐Cubero, 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, V.M. Van Deerlin, Murray Grossman, John Q. Trojanowski, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Stefano F. Cappa, Isabelle Leber, Didier Hannequin, Véronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jørgen E. Nielsen, L. E. Hjermind, Markus J. Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Maria Grazia Spillantini, Huw R. Morris, Patrizia Rizzu, Peter Heutink, Julie S. Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, 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, Caroline Graff, Ronald Petersen, David S. Knopman, K. Josephs, B. F. Boeve, J. E. Parisi, William W. Seeley, Bruce L. Miller, Anna M. Karydas, Howard J. Rosen, John C. van Swieten, Elise G.P. Dopper, Harro Seelaar, Yolande A.L. Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale Alessandro Puca, M. Franceschi, A. Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, H-H Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Thibaud Lebouvier, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering‐Brown, Andrew Singleton, John Hardy, Parastoo Momeni,

Immune cells in cancer

Abstract Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12 , TLR2, RALB, and CCR5 . Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT , we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.