CXCR4 involvement in neurodegenerative diseases

Bonham, L.W.; Karch, C.M.; Fan, C.C.; Tan, C.; Geier, E.G.; Wang, Y.; Wen, N.; Broce, I.J.; Yi, L.; 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.; Miller, B.L.; Andreassen, O.A.; Dale, A.M.; Barkovich, A.J.; Yokoyama, J.S.; Desikan, R.S.; Hernandez, D.G.; Nalls, M.A.; Rohrer, J.D.; Ramasamy, A.; Kwok, J.B.J.; Dobson-Stone, C.; Schofield, P.R.; Halliday, G.M.; Hodges, J.R.; Piguet, O.; Bartley, L.; Thompson, E.; Haan, E.; Hernández, I.; Ruiz, A.; Boada, M.; Borroni, B.; Padovani, A.; Cruchaga, C.; Cairns, N.J.; 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, M.L.; Nilsson, K.; Nilsson, C.; Mackenzie, I.R.A.; Hsiung, G.-.R.; Mann, D.M.A.; Grafman, J.; Morris, C.M.; Attems, J.; Griffiths, T.D.; Mckeith, I.G.; Thomas, A.J.; Pietrini, P.; Huey, E.D.; Wassermann, E.M.; Baborie, A.; Jaros, E.; Tierney, M.C.; 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, P.S.; Rossi, G.; Tagliavini, F.; Giaccone, G.; Rowe, J.B.; Schlachetzki, J.C.M.; Uphill, J.; Collinge, J.; Mead, S.; Danek, A.; Van Deerlin, V.M.; Grossman, M.; Trojanowski, J.Q.; Van Der Zee, J.; Cruts, M.; Van Broeckhoven, C.; Cappa, S.F.; Leber, I.; Hannequin, D.; Golfier, V.; Vercelletto, M.; Brice, A.; Nacmias, B.; Sorbi, S.; Bagnoli, S.; Piaceri, I.; Nielsen, J.E.; Hjermind, L.E.; Riemenschneider, M.; Mayhaus, M.; Ibach, B.; Gasparoni, G.; Pichler, S.; Gu, W.; Rossor, M.N.; Fox, N.C.; Warren, J.D.; Spillantini, M.G.; Morris, H.R.; Rizzu, P.; Heutink, P.; Snowden, J.S.; Rollinson, S.; Richardson, A.; Gerhard, A.; Bruni, A.C.; Maletta, R.; Frangipane, F.; Cupidi, C.; Bernardi, L.; Anfossi, M.; Gallo, M.; Conidi, M.E.; Smirne, N.; Rademakers, R.; Baker, M.; Dickson, D.W.; Graff-Radford, N.R.; Petersen, R.C.; Knopman, D.; Josephs, K.A.; Boeve, B.F.; Parisi, J.E.; Seeley, W.W.; Karydas, A.M.; Rosen, H.; Van Swieten, J.C.; Dopper, E.G.P.; Seelaar, H.; Pijnenburg, Y.A.L.; Scheltens, P.; Logroscino, G.; Capozzo, R.; Novelli, V.; Puca, A.A.; Franceschi, M.; Postiglione, A.; Milan, G.; Sorrentino, P.; Kristiansen, M.; Chiang, H.-.; Graff, C.; Pasquier, F.; Rollin, A.; Deramecourt, V.; Lebouvier, T.; Kapogiannis, D.; Ferrucci, L.; Pickering-Brown, S.; Singleton, A.B.

doi:10.1038/s41398-017-0049-7

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.

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.-.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.-. Chiang, C. Graff, F. Pasquier, A. Rollin, V. Deramecourt, T. Lebouvier, D. Kapogiannis, L. Ferrucci, S. Pickering-Brown, A.B. Singleton. - In: TRANSLATIONAL PSYCHIATRY. - ISSN 2158-3188. - 8:1(2018), pp. 73.1-73.10.

CXCR4 involvement in neurodegenerative diseases

Bonham, Luke W.;Karch, Celeste M.;Fan, Chun C.;Tan, Chin;Geier, Ethan G.;Wang, Yunpeng;Wen, Natalie;Broce, Iris J.;Li, Yi;Barkovich, Matthew J.;Ferrari, Raffaele;Hardy, John;Momeni, Parastoo;Höglinger, Günter;Müller, Ulrich;Hess, Christopher P.;Sugrue, Leo P.;Dillon, William P.;Schellenberg, Gerard D.;Miller, Bruce L.;Andreassen, Ole A.;Dale, Anders M.;Barkovich, A. James;Yokoyama, Jennifer S.;Desikan, Rahul S.;Hernandez, D. G.;Nalls, M. A.;Rohrer, J. D.;Ramasamy, A.;Kwok, J. B. J.;Dobson-Stone, C.;Schofield, P. R.;Halliday, G. M.;Hodges, J. R.;Piguet, O.;Bartley, L.;Thompson, E.;Haan, E.;Hernández, I.;Ruiz, A.;Boada, M.;Borroni, B.;Padovani, A.;Cruchaga, C.;Cairns, N. J.;Benussi, L.;Binetti, G.;Ghidoni, R.;Forloni, G.;Albani, D.;D. Galimberti;C. Fenoglio;M. Serpente;E. Scarpini;Clarimón, J.;Lleó, A.;Blesa, R.;Waldö, M. Landqvist.;Nilsson, K.;Nilsson, C.;MacKenzie, I. R. A.;Hsiung, G. -Y. R.;Mann, D. M. A.;Grafman, J.;Morris, C. M.;Attems, J.;Griffiths, T. D.;McKeith, I. G.;Thomas, A. J.;Pietrini, P.;Huey, E. D.;Wassermann, E. M.;Baborie, A.;Jaros, E.;Tierney, M. C.;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, P. St.;Rossi, G.;Tagliavini, F.;Giaccone, G.;Rowe, J. B.;Schlachetzki, J. C. M.;Uphill, J.;Collinge, J.;Mead, S.;Danek, A.;Van Deerlin, V. M.;Grossman, M.;Trojanowski, J. Q.;Van Der Zee, J.;Cruts, M.;Van Broeckhoven, C.;Cappa, S. F.;Leber, I.;Hannequin, D.;Golfier, V.;Vercelletto, M.;Brice, A.;Nacmias, B.;Sorbi, S.;Bagnoli, S.;Piaceri, I.;Nielsen, J. E.;Hjermind, L. E.;Riemenschneider, M.;Mayhaus, M.;Ibach, B.;Gasparoni, G.;Pichler, S.;Gu, W.;Rossor, M. N.;Fox, N. C.;Warren, J. D.;Spillantini, M. G.;Morris, H. R.;Rizzu, P.;Heutink, P.;Snowden, J. S.;Rollinson, S.;Richardson, A.;Gerhard, A.;Bruni, A. C.;Maletta, R.;Frangipane, F.;Cupidi, C.;Bernardi, L.;Anfossi, M.;Gallo, M.;Conidi, M. E.;Smirne, N.;Rademakers, R.;Baker, M.;Dickson, D. W.;Graff-Radford, N. R.;Petersen, R. C.;Knopman, D.;Josephs, K. A.;Boeve, B. F.;Parisi, J. E.;Seeley, W. W.;Karydas, A. M.;Rosen, H.;Van Swieten, J. C.;Dopper, E. G. P.;Seelaar, H.;Pijnenburg, Y. A. L.;Scheltens, P.;Logroscino, G.;Capozzo, R.;Novelli, V.;Puca, A. A.;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, A. B.

2018

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.

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	Parole chiave
	
				Progressive supranuclear palsy; chemokine receptor CXCR4; predicting gene-function; genome-wide association; Parkinsons-disease; frontotemporal dementia; Alzheimers-disease; network integration; alpha-syneclein; expression
			
	Settori scientifico-disciplinari dell'articolo (sola visualizzazione)
	
				Settore BIO/13 - Biologia Applicata
Settore MED/26 - Neurologia
			
	Data di pubblicazione
	
				2018
			
	Rivista in ANCE
	
				TRANSLATIONAL PSYCHIATRY
			
	DOI
	
				https://dx.doi.org/10.1038/s41398-017-0049-7
			
	Tipologia
	
				Article (author)
			
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				01 - Articolo su periodico

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