CXCR4involvement in neurodegenerative diseases
Copyright policy )CXCR4involvement in neurodegenerative diseases
ABSTRACTNeurodegenerative 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 theMAPTH1 haplotype, we identified a variant near the chemokine receptorCXCR4that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions betweenCXCR4and four microglia related genes, namelyCXCL12,TLR2, RALBandCCR5.Evaluating gene expression from post-mortem brain tissue, we found that expression ofCXCR4and microglial genes functionally related toCXCR4was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression ofCXCR4and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. BeyondMAPT, we show dysregulation ofCXCR4expression 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.
- Ludwig-Maximilians-Universität München Germany
- Technical University of Munich Germany
- University College London United Kingdom
- University of California System United States
- University of Florence Italy
Aging, 5202 Biological Psychology, Gene Expression, 32 Biomedical and Clinical Sciences, Progressive supranuclear palsy; chemokine receptor CXCR4; predicting gene-function; genome-wide association; Parkinsons-disease; frontotemporal dementia; Alzheimers-disease; network integration; alpha-syneclein; expression, Neurodegenerative, metabolism [Microglia], Alzheimer's Disease, anzsrc-for: 1103 Clinical Sciences, Transgenic, Mice, Risk Factors, Receptors, Animals; Brain; Gene Expression; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Mice, Transgenic; Microglia; Neurodegenerative Diseases; Polymorphism, Single Nucleotide; Receptors, CXCR4; Risk Factors; Genetic Predisposition to Disease, 2.1 Biological and endogenous factors, Psychology, Gene Regulatory Networks, Aetiology, 3202 Clinical Sciences, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, International Genomics of Alzheimer’s Project, International Genomics of Alzheimer’s Project (IGAP), Medical genetics, Brain, Neurodegenerative Diseases, Single Nucleotide, International Parkinson’s Disease Genetics Consortium, Frontotemporal Dementia (FTD), Psychiatry and Mental Health, 52 Psychology, Neurological, Public Health and Health Services, anzsrc-for: 3209 Neurosciences, anzsrc-for: 3202 Clinical Sciences, Microglia, anzsrc-for: 5202 Biological Psychology, anzsrc-for: 1117 Public Health and Health Services, Receptors, CXCR4, Clinical Sciences, 610, Mice, Transgenic, Molecular neuroscience, Predictive markers, Polymorphism, Single Nucleotide, CXCR4 protein, human, Article, anzsrc-for: 52 Psychology, Cellular and Molecular Neuroscience, anzsrc-for: 32 Biomedical and Clinical Sciences, Rare Diseases, Genetics, Acquired Cognitive Impairment, Animals, Humans, Genetic Predisposition to Disease, Clinical genetics, Polymorphism, Biological Psychiatry, CXCR4, Psychiatry and Mental Health; Cellular and Molecular Neuroscience; Biological Psychiatry, International FTD-Genomics Consortium, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), anzsrc-for: 1701 Psychology, genetics [Receptors, CXCR4], Brain Disorders, Animals; Brain; Gene Expression; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Mice, Transgenic; Microglia; Neurodegenerative Diseases; Polymorphism, Single Nucleotide; Receptors, CXCR4; Risk Factors; Genetic Predisposition to Disease; Psychiatry and Mental Health; Cellular and Molecular Neuroscience; Biological Psychiatry, International Parkinson’s Disease Genetics Consortium (IPDGC), metabolism [Brain], genetics [Neurodegenerative Diseases], 3209 Neurosciences, Dementia, metabolism [Receptors, CXCR4], International FTD-Genomics Consortium (IFGC), Genome-Wide Association Study, ddc: ddc:610
Aging, 5202 Biological Psychology, Gene Expression, 32 Biomedical and Clinical Sciences, Progressive supranuclear palsy; chemokine receptor CXCR4; predicting gene-function; genome-wide association; Parkinsons-disease; frontotemporal dementia; Alzheimers-disease; network integration; alpha-syneclein; expression, Neurodegenerative, metabolism [Microglia], Alzheimer's Disease, anzsrc-for: 1103 Clinical Sciences, Transgenic, Mice, Risk Factors, Receptors, Animals; Brain; Gene Expression; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Mice, Transgenic; Microglia; Neurodegenerative Diseases; Polymorphism, Single Nucleotide; Receptors, CXCR4; Risk Factors; Genetic Predisposition to Disease, 2.1 Biological and endogenous factors, Psychology, Gene Regulatory Networks, Aetiology, 3202 Clinical Sciences, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, International Genomics of Alzheimer’s Project, International Genomics of Alzheimer’s Project (IGAP), Medical genetics, Brain, Neurodegenerative Diseases, Single Nucleotide, International Parkinson’s Disease Genetics Consortium, Frontotemporal Dementia (FTD), Psychiatry and Mental Health, 52 Psychology, Neurological, Public Health and Health Services, anzsrc-for: 3209 Neurosciences, anzsrc-for: 3202 Clinical Sciences, Microglia, anzsrc-for: 5202 Biological Psychology, anzsrc-for: 1117 Public Health and Health Services, Receptors, CXCR4, Clinical Sciences, 610, Mice, Transgenic, Molecular neuroscience, Predictive markers, Polymorphism, Single Nucleotide, CXCR4 protein, human, Article, anzsrc-for: 52 Psychology, Cellular and Molecular Neuroscience, anzsrc-for: 32 Biomedical and Clinical Sciences, Rare Diseases, Genetics, Acquired Cognitive Impairment, Animals, Humans, Genetic Predisposition to Disease, Clinical genetics, Polymorphism, Biological Psychiatry, CXCR4, Psychiatry and Mental Health; Cellular and Molecular Neuroscience; Biological Psychiatry, International FTD-Genomics Consortium, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), anzsrc-for: 1701 Psychology, genetics [Receptors, CXCR4], Brain Disorders, Animals; Brain; Gene Expression; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Mice, Transgenic; Microglia; Neurodegenerative Diseases; Polymorphism, Single Nucleotide; Receptors, CXCR4; Risk Factors; Genetic Predisposition to Disease; Psychiatry and Mental Health; Cellular and Molecular Neuroscience; Biological Psychiatry, International Parkinson’s Disease Genetics Consortium (IPDGC), metabolism [Brain], genetics [Neurodegenerative Diseases], 3209 Neurosciences, Dementia, metabolism [Receptors, CXCR4], International FTD-Genomics Consortium (IFGC), Genome-Wide Association Study, ddc: ddc:610
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).80 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!