WashU weekly Neuroscience publications

CXCR4 involvement in neurodegenerative diseases
(2018) Translational Psychiatry, 8 (1), art. no. 73, . 

Bonham, L.W.^a , Karch, C.M.^b , Fan, C.C.^c , Tan, C.^d , Geier, E.G.^a , Wang, Y.^e , Wen, N.^b , Broce, I.J.^d , Li, Y.^d , Barkovich, M.J.^d , Ferrari, R.^f , Hardy, J.^f , Momeni, P.^g , Höglinger, G.^{h i} , Müller, U.^j , Hess, C.P.^d , Sugrue, L.P.^d , Dillon, W.P.^d , Schellenberg, G.D.^k , Miller, B.L.^a , Andreassen, O.A.^e , Dale, A.M.^{c l} , Barkovich, A.J.^d , Yokoyama, J.S.^a , Desikan, R.S.^a , Hernandez, D.G.^m , Nalls, M.A.^m , Rohrer, J.D.^m , Ramasamy, A.^m , Kwok, J.B.J.^m , Dobson-Stone, C.^m , Schofield, P.R.^m , Halliday, G.M.^m , Hodges, J.R.^m , Piguet, O.^m , Bartley, L.^m , Thompson, E.^m , Haan, E.^m , Hernández, I.^m , Ruiz, A.^m , Boada, M.^m , Borroni, B.^m , Padovani, A.^m , Cruchaga, C.^m , Cairns, N.J.^m , Benussi, L.^m , Binetti, G.^m , Ghidoni, R.^m , Forloni, G.^m , Albani, D.^m , Galimberti, D.^m , Fenoglio, C.^m , Serpente, M.^m , Scarpini, E.^m , Clarimón, J.^m , Lleó, A.^m , Blesa, R.^m , Waldö, M.L.^m , Nilsson, K.^m , Nilsson, C.^m , MacKenzie, I.R.A.^m , Hsiung, G.-Y.R.^m , Mann, D.M.A.^m , Grafman, J.^m , Morris, C.M.^m , Attems, J.^m , Griffiths, T.D.^m , McKeith, I.G.^m , Thomas, A.J.^m , Pietrini, P.^m , Huey, E.D.^m , Wassermann, E.M.^m , Baborie, A.^m , Jaros, E.^m , Tierney, M.C.^m , Pastor, P.^m , Razquin, C.^m , Ortega-Cubero, S.^m , Alonso, E.^m , Perneczky, R.^m , Diehl-Schmid, J.^m , Alexopoulos, P.^m , Kurz, A.^m , Rainero, I.^m , Rubino, E.^m , Pinessi, L.^m , Rogaeva, E.^m , George-Hyslop, P.S.^m , Rossi, G.^m , Tagliavini, F.^m , Giaccone, G.^m , Rowe, J.B.^m , Schlachetzki, J.C.M.^m , Uphill, J.^m , Collinge, J.^m , Mead, S.^m , Danek, A.^m , Van Deerlin, V.M.^m , Grossman, M.^m , Trojanowski, J.Q.^m , Van Der Zee, J.^m , Cruts, M.^m , Van Broeckhoven, C.^m , Cappa, S.F.^m , Leber, I.^m , Hannequin, D.^m , Golfier, V.^m , Vercelletto, M.^m , Brice, A.^m , Nacmias, B.^m , Sorbi, S.^m , Bagnoli, S.^m , Piaceri, I.^m , Nielsen, J.E.^m , Hjermind, L.E.^m , Riemenschneider, M.^m , Mayhaus, M.^m , Ibach, B.^m , Gasparoni, G.^m , Pichler, S.^m , Gu, W.^m , Rossor, M.N.^m , Fox, N.C.^m , Warren, J.D.^m , Spillantini, M.G.^m , Morris, H.R.^m , Rizzu, P.^m , Heutink, P.^m , Snowden, J.S.^m , Rollinson, S.^m , Richardson, A.^m , Gerhard, A.^m , Bruni, A.C.^m , Maletta, R.^m , Frangipane, F.^m , Cupidi, C.^m , Bernardi, L.^m , Anfossi, M.^m , Gallo, M.^m , Conidi, M.E.^m , Smirne, N.^m , Rademakers, R.^m , Baker, M.^m , Dickson, D.W.^m , Graff-Radford, N.R.^m , Petersen, R.C.^m , Knopman, D.^m , Josephs, K.A.^m , Boeve, B.F.^m , Parisi, J.E.^m , Seeley, W.W.^m , Karydas, A.M.^m , Rosen, H.^m , Van Swieten, J.C.^m , Dopper, E.G.P.^m , Seelaar, H.^m , Pijnenburg, Y.A.L.^m , Scheltens, P.^m , Logroscino, G.^m , Capozzo, R.^m , Novelli, V.^m , Puca, A.A.^m , Franceschi, M.^m , Postiglione, A.^m , Milan, G.^m , Sorrentino, P.^m , Kristiansen, M.^m , Chiang, H.-H.^m , Graff, C.^m , Pasquier, F.^m , Rollin, A.^m , Deramecourt, V.^m , Lebouvier, T.^m , Kapogiannis, D.^m , Ferrucci, L.^m , Pickering-Brown, S.^m , Singleton, A.B.^m , International FTD-Genomics Consortium (IFGC), International Parkinson’s Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer’s Project (IGAP)^m

^a Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
^b Department of Psychiatry, Washington University, St. Louis, MO, United States
^c Department of Cognitive Sciences, University of California CA, San Diego, CA, United States
^d Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA, United States
^e NORMENT, Institute of Clinical Medicine, University of Oslo, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
^f Department of Molecular Neuroscience, Institute of Neurology, UCL, London, United Kingdom
^g Department of Internal Medicine, Laboratory of Neurogenetics, Texas Tech University Health Science Center, Lubbock, TX, United States
^h Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
ⁱ Department of Neurology, Technical University of Munich, Munich Cluster for Systems Neurology SyNergy, Munich, Germany
^j Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany
^k Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^l Department of Neurosciences and Radiology, University of California, San Diego, CA, United States

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. © 2017 The Author(s).

Document Type: Article
Source: Scopus