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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.
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.
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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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/635445
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Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
