CXCR4 involvement in neurodegenerative diseases

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

Research output: Contribution to journalArticle

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).
Original languageEnglish
JournalTranslational Psychiatry
Volume8
Issue number1
DOIs
Publication statusPublished - 2018

Keywords

  • chemokine receptor CCR5
  • chemokine receptor CXCR4
  • tau protein
  • toll like receptor 2
  • CXCR4 protein, human, Alzheimer disease
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • bioinformatics
  • brain tissue
  • controlled study
  • degenerative disease
  • expression quantitative trait locus
  • frontotemporal dementia
  • gene expression
  • genetic risk
  • genome-wide association study
  • haplotype
  • human
  • human tissue
  • major clinical study
  • microglia
  • mouse
  • nerve degeneration
  • nonhuman
  • Parkinson disease
  • pleiotropy
  • progressive supranuclear palsy
  • protein protein interaction
  • tauopathy
  • animal
  • brain
  • gene regulatory network
  • genetic predisposition
  • genetics
  • metabolism
  • risk factor
  • single nucleotide polymorphism
  • transgenic mouse, Animals
  • Brain
  • Gene Expression
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Mice, Transgenic
  • Microglia
  • Neurodegenerative Diseases
  • Polymorphism, Single Nucleotide
  • Receptors, CXCR4
  • Risk Factors

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    Bonham, L. W., Karch, C. M., Fan, C. C., Tan, C., Geier, E. G., Wang, Y., Wen, N., Broce, I. J., Li, Y., Barkovich, M. J., Ferrari, R., Hardy, J., Momeni, P., Höglinger, G., Müller, U., Hess, C. P., Sugrue, L. P., Dillon, W. P., Schellenberg, G. D., ... International FTD-Genomics Consortium (IFGC) International Parkinson's Disease Genetics Consortium (IPDGC), I. G. O. A. P. IGAP. (2018). CXCR4 involvement in neurodegenerative diseases. Translational Psychiatry, 8(1). https://doi.org/10.1038/s41398-017-0049-7