CXCR4 involvement in neurodegenerative diseases

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Article number73
JournalTranslational psychiatry
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Progressive Supranuclear Palsy
Neurodegenerative Diseases
Parkinson Disease
Frontotemporal Dementia
Brain
Tauopathies
Genes
Neurofibrillary Tangles
Gene Regulatory Networks
Chemokine Receptors
Microglia
Computational Biology
Haplotypes
Dementia
Alzheimer Disease
Clinical Trials
Genome
Pathology
Gene Expression

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP) (2018). CXCR4 involvement in neurodegenerative diseases. Translational psychiatry, 8(1), [73]. https://doi.org/10.1038/s41398-017-0049-7
International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP). / CXCR4 involvement in neurodegenerative diseases. In: Translational psychiatry. 2018 ; Vol. 8, No. 1.
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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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International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP) 2018, 'CXCR4 involvement in neurodegenerative diseases', Translational psychiatry, vol. 8, no. 1, 73. https://doi.org/10.1038/s41398-017-0049-7

CXCR4 involvement in neurodegenerative diseases. / International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP).

In: Translational psychiatry, Vol. 8, No. 1, 73, 01.12.2018.

Research output: Contribution to journalArticle

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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 - Grafman, Jordan Henry

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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.

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International FTD-Genomics Consortium (IFGC), International Parkinson's Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer's Project (IGAP). CXCR4 involvement in neurodegenerative diseases. Translational psychiatry. 2018 Dec 1;8(1). 73. https://doi.org/10.1038/s41398-017-0049-7