CXCR4 involvement in neurodegenerative diseases

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.

Fig. 1. Shared genetic risk across PSP, AD, FTD and PD

a Fold enrichment plots of enrichment vs. nominal −log₁₀ p-values (corrected for inflation) in progressive supranuclear palsy (PSP) below the standard GWAS threshold of p < 5 × 10^-8 as a function of significance of association with Alzheimer’s disease (AD, panel A), frontotemporal dementia (FTD, panel B) and Parkinson’s disease (PD, panel C) at the level of −log₁₀(p) ≥ 0, −log₁₀(p) ≥ 1, −log₁₀(p) ≥ 2 corresponding to p ≤ 1, p ≤ 0.1, p ≤ 0.01, respectively. Blue line indicates all SNPs. b “Conjunction” Manhattan plot of conjunction and conditional –log₁₀ (FDR) values for progressive supranuclear palsy (PSP) given Alzheimer’s disease (AD; PSP|AD, teal), frontotemporal dementia (PSP; PSP|FTD, orange) and Parkinson’s disease (PD; PSP|PD, red). SNPs with conditional and conjunction –log₁₀ FDR > 1.3 (i.e., FDR < 0.05) are shown with large points. A black line around the large points indicates the most significant SNP in each LD block and this SNP was annotated with the closest gene, which is listed above the symbols in each locus. c Network interaction graph illustrating physical interactions, co-expression, predicted, pathway, co-localization, gene interactions and shared protein domains for CXCR4 and MAPT. Network plot was generated from GeneMANIA (www.genemania.org)

Fig. 2. CXCR4 is differentially expressed in human neurodegenerative diseases and in mouse models of tauopathies

a CXCR4 expression in neuropathologically normal tissue compared to PSP. b CXCR4 expression in neuropathologically normal tissue compared to sporadic FTD and FTD due to GRN mutations. (c) CXCR4 expression in neuropathologically normal tissue compared to PD. d-e Line plots illustrating CXCR4 gene expression in tau transgenic (red line) and wild-type mice (black line) from 2 to 18 months of age in the d hippocampus. e Total tau pathology over time is also illustrated