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. Miller; O.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)

doi:10.1038/s41398-017-0049-7

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 journal › Article › peer-review

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 language	English
Journal	Translational Psychiatry
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41398-017-0049-7
Publication status	Published - 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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10.1038/s41398-017-0049-7

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85045350217&doi=10.1038%2fs41398-017-0049-7&partnerID=40&md5=3c911b9772dc36f638210e4f9d5f3946

Cite this

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. (2018). CXCR4 involvement in neurodegenerative diseases. Translational Psychiatry, 8(1). https://doi.org/10.1038/s41398-017-0049-7

Bonham, LW, Karch, CM, Fan, CC, Tan, C, Geier, EG, Wang, Y, Wen, N, Broce, IJ, Li, Y, Barkovich, MJ, Ferrari, R, Hardy, J, Momeni, P, Höglinger, G, Müller, U, Hess, CP, Sugrue, LP, Dillon, WP, Schellenberg, GD, Miller, BL, Andreassen, OA, Dale, AM, Barkovich, AJ, Yokoyama, JS, Desikan, RS, 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, G-YR, 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, 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, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, AB & International FTD-Genomics Consortium (IFGC) International Parkinson's Disease Genetics Consortium (IPDGC), IGOAP 2018, 'CXCR4 involvement in neurodegenerative diseases', Translational Psychiatry, vol. 8, no. 1. https://doi.org/10.1038/s41398-017-0049-7

@article{fe83ffe72db24ac095ad53f66c4e61ea,

title = "CXCR4 involvement in neurodegenerative diseases",

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. {\textcopyright} 2017 The Author(s).",

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",

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

note = "cited By 1",

year = "2018",

doi = "10.1038/s41398-017-0049-7",

language = "English",

volume = "8",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - CXCR4 involvement in neurodegenerative diseases

AU - Bonham, L.W.

AU - Karch, C.M.

AU - Fan, C.C.

AU - Tan, C.

AU - Geier, E.G.

AU - Wang, Y.

AU - Wen, N.

AU - Broce, I.J.

AU - Li, Y.

AU - Barkovich, M.J.

AU - Ferrari, R.

AU - Hardy, J.

AU - Momeni, P.

AU - Höglinger, G.

AU - Müller, U.

AU - Hess, C.P.

AU - Sugrue, L.P.

AU - Dillon, W.P.

AU - Schellenberg, G.D.

AU - Miller, B.L.

AU - Andreassen, O.A.

AU - Dale, A.M.

AU - Barkovich, A.J.

AU - Yokoyama, J.S.

AU - Desikan, R.S.

AU - Hernandez, D.G.

AU - Nalls, M.A.

AU - Rohrer, J.D.

AU - Ramasamy, A.

AU - Kwok, J.B.J.

AU - Dobson-Stone, C.

AU - Schofield, P.R.

AU - Halliday, G.M.

AU - Hodges, J.R.

AU - Piguet, O.

AU - Bartley, L.

AU - Thompson, E.

AU - Haan, E.

AU - Hernández, I.

AU - Ruiz, A.

AU - Boada, M.

AU - Borroni, B.

AU - Padovani, A.

AU - Cruchaga, C.

AU - Cairns, N.J.

AU - Benussi, L.

AU - Binetti, G.

AU - Ghidoni, R.

AU - Forloni, G.

AU - Albani, D.

AU - Galimberti, D.

AU - Fenoglio, C.

AU - Serpente, M.

AU - Scarpini, E.

AU - Clarimón, J.

AU - Lleó, A.

AU - Blesa, R.

AU - Waldö, M.L.

AU - Nilsson, K.

AU - Nilsson, C.

AU - MacKenzie, I.R.A.

AU - Hsiung, G.-Y.R.

AU - Mann, D.M.A.

AU - Grafman, J.

AU - Morris, C.M.

AU - Attems, J.

AU - Griffiths, T.D.

AU - McKeith, I.G.

AU - Thomas, A.J.

AU - Pietrini, P.

AU - Huey, E.D.

AU - Wassermann, E.M.

AU - Baborie, A.

AU - Jaros, E.

AU - Tierney, M.C.

AU - Pastor, P.

AU - Razquin, C.

AU - Ortega-Cubero, S.

AU - Alonso, E.

AU - Perneczky, R.

AU - Diehl-Schmid, J.

AU - Alexopoulos, P.

AU - Kurz, A.

AU - Rainero, I.

AU - Rubino, E.

AU - Pinessi, L.

AU - Rogaeva, E.

AU - George-Hyslop, P.S.

AU - Rossi, G.

AU - Tagliavini, F.

AU - Giaccone, G.

AU - Rowe, J.B.

AU - Schlachetzki, J.C.M.

AU - Uphill, J.

AU - Collinge, J.

AU - Mead, S.

AU - Danek, A.

AU - Van Deerlin, V.M.

AU - Grossman, M.

AU - Trojanowski, J.Q.

AU - Van Der Zee, J.

AU - Cruts, M.

AU - Van Broeckhoven, C.

AU - Cappa, S.F.

AU - Leber, I.

AU - Hannequin, D.

AU - Golfier, V.

AU - Vercelletto, M.

AU - Brice, A.

AU - Nacmias, B.

AU - Sorbi, S.

AU - Bagnoli, S.

AU - Piaceri, I.

AU - Nielsen, J.E.

AU - Hjermind, L.E.

AU - Riemenschneider, M.

AU - Mayhaus, M.

AU - Ibach, B.

AU - Gasparoni, G.

AU - Pichler, S.

AU - Gu, W.

AU - Rossor, M.N.

AU - Fox, N.C.

AU - Warren, J.D.

AU - Spillantini, M.G.

AU - Morris, H.R.

AU - Rizzu, P.

AU - Heutink, P.

AU - Snowden, J.S.

AU - Rollinson, S.

AU - Richardson, A.

AU - Gerhard, A.

AU - Bruni, A.C.

AU - Maletta, R.

AU - Frangipane, F.

AU - Cupidi, C.

AU - Bernardi, L.

AU - Anfossi, M.

AU - Gallo, M.

AU - Conidi, M.E.

AU - Smirne, N.

AU - Rademakers, R.

AU - Baker, M.

AU - Dickson, D.W.

AU - Graff-Radford, N.R.

AU - Petersen, R.C.

AU - Knopman, D.

AU - Josephs, K.A.

AU - Boeve, B.F.

AU - Parisi, J.E.

AU - Seeley, W.W.

AU - Karydas, A.M.

AU - Rosen, H.

AU - Van Swieten, J.C.

AU - Dopper, E.G.P.

AU - Seelaar, H.

AU - Pijnenburg, Y.A.L.

AU - Scheltens, P.

AU - Logroscino, G.

AU - Capozzo, R.

AU - Novelli, V.

AU - Puca, A.A.

AU - Franceschi, M.

AU - Postiglione, A.

AU - Milan, G.

AU - Sorrentino, P.

AU - Kristiansen, M.

AU - Chiang, H.-H.

AU - Graff, C.

AU - Pasquier, F.

AU - Rollin, A.

AU - Deramecourt, V.

AU - Lebouvier, T.

AU - Kapogiannis, D.

AU - Ferrucci, L.

AU - Pickering-Brown, S.

AU - Singleton, A.B.

AU - International FTD-Genomics Consortium (IFGC) International Parkinson's Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP)

N1 - cited By 1

PY - 2018

Y1 - 2018

N2 - 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).

AB - 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).

KW - chemokine receptor CCR5

KW - chemokine receptor CXCR4

KW - tau protein

KW - toll like receptor 2

KW - CXCR4 protein, human, Alzheimer disease

KW - animal experiment

KW - animal model

KW - animal tissue

KW - Article

KW - bioinformatics

KW - brain tissue

KW - controlled study

KW - degenerative disease

KW - expression quantitative trait locus

KW - frontotemporal dementia

KW - gene expression

KW - genetic risk

KW - genome-wide association study

KW - haplotype

KW - human

KW - human tissue

KW - major clinical study

KW - microglia

KW - mouse

KW - nerve degeneration

KW - nonhuman

KW - Parkinson disease

KW - pleiotropy

KW - progressive supranuclear palsy

KW - protein protein interaction

KW - tauopathy

KW - animal

KW - brain

KW - gene regulatory network

KW - genetic predisposition

KW - genetics

KW - metabolism

KW - risk factor

KW - single nucleotide polymorphism

KW - transgenic mouse, Animals

KW - Brain

KW - Gene Expression

KW - Gene Regulatory Networks

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Mice, Transgenic

KW - Microglia

KW - Neurodegenerative Diseases

KW - Polymorphism, Single Nucleotide

KW - Receptors, CXCR4

KW - Risk Factors

U2 - 10.1038/s41398-017-0049-7

DO - 10.1038/s41398-017-0049-7

M3 - Article

SN - 2158-3188

VL - 8

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

ER -

CXCR4 involvement in neurodegenerative diseases

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