Format

Send to

Choose Destination
Transl Psychiatry. 2018 Apr 11;8(1):73. doi: 10.1038/s41398-017-0049-7.

CXCR4 involvement in neurodegenerative diseases.

Collaborators (156)

Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, George-Hyslop PS, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Cruts M, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P.

Author information

1
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
2
Department of Psychiatry, Washington University, St. Louis, MO, USA.
3
Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA.
4
Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA, USA.
5
NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
6
Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
7
Department of Internal Medicine, Laboratory of Neurogenetics, Texas Tech University Health Science Center, Lubbock, TX, USA.
8
Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
9
Department of Neurology, Technical University of Munich; Munich Cluster for Systems Neurology SyNergy, Munich, Germany.
10
Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
11
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
12
Department of Neurosciences and Radiology, University of California, San Diego, La Jolla, CA, USA.
13
Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA, USA. rahul.desikan@ucsf.edu.

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.

PMID:
29636460
PMCID:
PMC5893558
DOI:
10.1038/s41398-017-0049-7
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center