CXCR4 involvement in neurodegenerative diseases.
CXCR4 involvement in neurodegenerative diseases.
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DOI：
10.1038/s41398-017-0049-7
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发表时间：
2018-04-11
影响因子：
6.8
通讯作者：
International Genomics of Alzheimer’s Project (IGAP)
中科院分区：
文献类型：
--
作者：
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;Barkovich AJ;Yokoyama JS;Desikan RS;International FTD-Genomics Consortium (IFGC);International Parkinson’s Disease Genetics Consortium (IPDGC);International Genomics of Alzheimer’s Project (IGAP)
神经退行性疾病可能具有共同的基础病理学。尽管之前的工作已经确定了与各种痴呆症相关的易感位点，但很少有研究系统地评估了几种神经退行性疾病的共同遗传风险。利用大型研究（总计 n = 82,337 例病例和对照）的全基因组关联数据，我们利用先前经过验证的方法来识别遗传重叠并揭示进行性核上性麻痹 (PSP)、额颞叶痴呆 (FTD)、帕金森病 (PD) 和阿尔茨海默病 (AD) 之间的共同途径。除了 MAPT H1 单倍型之外，我们还发现了趋化因子受体 CXCR4 附近的一个变异，该变异与 PSP 和 PD 风险增加共同相关。使用生物信息学工具，我们发现 CXCR4 和四个小胶质细胞相关基因（即 CXCL12、TLR2、RALB 和 CCR5）之间存在强烈的物理相互作用。通过评估死后脑组织的基因表达，我们发现 CXCR4 和与 CXCR4 功能相关的小胶质细胞基因的表达在许多神经退行性疾病中失调。此外，在 tau 蛋白病小鼠模型中，CXCR4 和功能相关基因的表达在小鼠大脑中神经原纤维缠结最严重的区域显着改变。除了 MAPT 之外，我们还发现 PSP、PD 和 FTD 大脑以及 tau 病理小鼠模型中 CXCR4 表达失调。我们的多模式研究结果表明，小胶质细胞基因“网络”上的异常信号传导可能会导致神经退行性变，并可能对针对神经退行性疾病患者免疫功能障碍的临床试验产生潜在影响。
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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DOI：
10.1016/s1474-4422(17)30157-6
发表时间：
2017-07
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Boxer AL;Yu JT;Golbe LI;Litvan I;Lang AE;Höglinger GU
通讯作者：
Höglinger GU
影响因子：
16.6
作者：
Arno, Benedetta;Grassivaro, Francesca;Muzio, Luca
通讯作者：
Muzio, Luca
影响因子：
3.5
作者：
Baker, M;Litvan, I;Hutton, M
通讯作者：
Hutton, M
影响因子：
5.3
作者：
Carbonell, WS;Murase, SI;Mandell, JW
通讯作者：
Mandell, JW
影响因子：
3.5
作者：
Chen-Plotkin, Alice S.;Geser, Felix;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.