TY - JOUR
T1 - CXCR4 involvement in neurodegenerative diseases
AU - International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP)
AU - Bonham, Luke W.
AU - Karch, Celeste M.
AU - Fan, Chun C.
AU - Tan, Chin
AU - Geier, Ethan G.
AU - Wang, Yunpeng
AU - Wen, Natalie
AU - Broce, Iris J.
AU - Li, Yi
AU - Barkovich, Matthew J.
AU - Ferrari, Raffaele
AU - Hardy, John
AU - Momeni, Parastoo
AU - Höglinger, Günter
AU - Müller, Ulrich
AU - Hess, Christopher P.
AU - Sugrue, Leo P.
AU - Dillon, William P.
AU - Schellenberg, Gerard D.
AU - Miller, Bruce L.
AU - Andreassen, Ole A.
AU - Dale, Anders M.
AU - Barkovich, A. James
AU - Yokoyama, Jennifer S.
AU - Desikan, Rahul 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 - Diehl-Schmid, J.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85045350217&partnerID=8YFLogxK
U2 - 10.1038/s41398-017-0049-7
DO - 10.1038/s41398-017-0049-7
M3 - Article
C2 - 29636460
AN - SCOPUS:85045350217
SN - 2158-3188
VL - 8
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 73
ER -