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Title | CXCR4 involvement in neurodegenerative diseases. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Bonham LW, Karch CM, Fan CC, Tan C, Geier EG, Wang Y, Wen N, Broce IJ, Li Y, Barkovich MJ, Ferrari R, Hardy J, Momeni P, Höglinger G, Müller U, Hess CP, Sugrue LP, Dillon WP, Schellenberg GD, Miller BL, Andreassen OA, Dale AM, A Barkovich J, Yokoyama JS, Desikan RS |
Corporate Authors | International FTD-Genomics Consortium(IFGC), International Parkinson’s Disease Genetics Consortium(IPDGC), International Genomics of Alzheimer’s Project(IGAP) |
Journal | Transl Psychiatry |
Volume | 8 |
Issue | 1 |
Pagination | 73 |
Date Published | 2018 04 11 |
ISSN | 2158-3188 |
Keywords | Animals, Brain, Gene Expression, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Transgenic, Microglia, Neurodegenerative Diseases, Polymorphism, Single Nucleotide, Receptors, CXCR4, Risk Factors |
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. |
DOI | 10.1038/s41398-017-0049-7 |
Alternate Journal | Transl Psychiatry |
PubMed ID | 29636460 |
PubMed Central ID | PMC5893558 |
Grant List | MC_UU_00024/1 / MRC_ / Medical Research Council / United Kingdom MC_U105597119 / MRC_ / Medical Research Council / United Kingdom G0900652 / MRC_ / Medical Research Council / United Kingdom G0400074 / MRC_ / Medical Research Council / United Kingdom MC_UU_00005/12 / MRC_ / Medical Research Council / United Kingdom K01 AG049152 / AG / NIA NIH HHS / United States G1100540 / MRC_ / Medical Research Council / United Kingdom MC_U123160657 / MRC_ / Medical Research Council / United Kingdom P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States K01 AG046374 / AG / NIA NIH HHS / United States G0502157 / MRC_ / Medical Research Council / United Kingdom |