Journal article
CXCR4 involvement in neurodegenerative diseases
Translational psychiatry, Vol.8(1), 73
04/11/2018
DOI: 10.1038/s41398-017-0049-7
PMCID: PMC5893558
PMID: 29636460
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.
Details
- Title: Subtitle
- CXCR4 involvement in neurodegenerative diseases
- Creators
- Luke W Bonham - University Memory and Aging CenterCeleste M Karch - Washington University in St. LouisChun C Fan - University of California, San DiegoChin Tan - University of California, San FranciscoEthan G Geier - University Memory and Aging CenterYunpeng Wang - Oslo University HospitalNatalie Wen - Washington University in St. LouisIris J Broce - University of California, San FranciscoYi Li - University of California, San FranciscoMatthew J Barkovich - University of California, San FranciscoRaffaele Ferrari - University College LondonJohn Hardy - University College LondonParastoo Momeni - Texas Tech University Health Sciences CenterGünter Höglinger - German Center for Neurodegenerative DiseasesUlrich Müller - University of GiessenChristopher P Hess - University of California, San FranciscoLeo P Sugrue - University of California, San FranciscoWilliam P Dillon - University of California, San FranciscoGerard D Schellenberg - University of PennsylvaniaBruce L Miller - University of California, San FranciscoOle A Andreassen - Oslo University HospitalAnders M Dale - University of California, San DiegoA James Barkovich - University of California, San FranciscoJennifer S Yokoyama - University Memory and Aging CenterRahul S Desikan - University of California, San FranciscoInternational FTD-Genomics Consortium (IFGC)International Parkinson’s Disease Genetics Consortium (IPDGC)International Genomics of Alzheimer’s Project (IGAP)Timothy Griffiths (Contributor) - Psychological and Brain Sciences
- Resource Type
- Journal article
- Publication Details
- Translational psychiatry, Vol.8(1), 73
- DOI
- 10.1038/s41398-017-0049-7
- PMID
- 29636460
- PMCID
- PMC5893558
- ISSN
- 2158-3188
- eISSN
- 2158-3188
- Grant note
- P01 AG003991 / NIA NIH HHS MC_U105597119 / Medical Research Council K01 AG046374 / NIA NIH HHS K01 AG049152 / NIA NIH HHS G0502157 / Medical Research Council P50 AG005681 / NIA NIH HHS G0301152 / Medical Research Council G1100540 / Medical Research Council MC_U123160657 / Medical Research Council MC_UU_00005/12 / Medical Research Council G0400074 / Medical Research Council MC_UU_00024/9 / Medical Research Council G0900652 / Medical Research Council MC_UU_00024/1 / Medical Research Council
- Language
- English
- Date published
- 04/11/2018
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627303802771
Metrics
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