Identification of gene networks mediating regional resistance to tauopathy in late-onset Alzheimer's disease.
Identification of gene networks mediating regional resistance to tauopathy in late-onset Alzheimer's disease.
复制标题
迟发性阿尔茨海默病中介导局部抗牛头病的基因网络的鉴定。
DOI：
10.1371/journal.pgen.1010681
复制
发表时间：
2023-03
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
由tau蛋白聚集物组成的神经原纤维病变是阿尔茨海默病的标志。尽管tau蛋白丝似乎以朊病毒样的方式在网络脑区域之间传播，但包括小脑在内的某些区域抵抗tau病的跨突触传播及其组成神经元细胞体的变性。为了确定耐药的分子相关因素，我们推导并实施了一种比率方法，以区域易感性为基础，分解基因表达数据。当应用于脆弱的前额叶皮层作为抗性小脑的内部参考时，该方法将表达的适应性变化分为两个部分。第一个富集了与蛋白质停滞相关的神经元来源转录本，包括分子伴侣家族的特定成员，并且是抗性小脑所特有的。当作为纯化蛋白生产时，鉴定出的每个伴侣蛋白在体外以亚化学计量浓度抑制2N4R tau的聚集，这与从比率测试中推断出的表达极性一致。相反，第二种成分富含与神经炎症相关的胶质细胞和小胶质细胞来源的转录本，将这些途径从易感性中分离出来。这些数据支持比值测试的效用，以建立相对于选择性易感性的基因表达变化的极性。这种方法有可能确定药物发现的新靶点，基于它们促进易感神经元群体对疾病的抵抗力的能力。阿尔茨海默病（AD）的部分定义是由tau蛋白组成的神经元内聚集体的出现。因为它们在大脑中的传播与认知能力下降和神经退行性变相关，所以tau病变可以作为疾病分期和识别神经细胞群对AD发病机制的易感性或抗性差异的标志物。在这里，我们比较了人类大脑脆弱区域的抗性，以确定相关的分子特征及其与通过大规模人类遗传学研究推断的危险因素的关系。我们发现，与防止细胞内蛋白错误折叠和聚集相关的基因的表达伴随着抗性，并且变化的幅度与脑连接区域中出现的tau负荷直接相关。耐药还伴随着两个经过验证的AD风险基因的表达变化，这些基因重现了遗传分析报告的方向性。这些数据支持使用选择性易感性来询问AD中基因表达变化的方向性，并识别对tau病理产生抗性的候选介质。
Neurofibrillary lesions composed of tau protein aggregates are defining hallmarks of Alzheimer’s Disease. Despite tau filaments appearing to spread between networked brain regions in a prion-like manner, certain areas including cerebellum resist trans-synaptic spread of tauopathy and degeneration of their constituent neuronal cell bodies. To identify molecular correlates of resistance, we derived and implemented a ratio of ratios approach for disaggregating gene expression data on the basis of regional vulnerability to tauopathic neurodegeneration. When applied to vulnerable pre-frontal cortex as an internal reference for resistant cerebellum, the approach segregated adaptive changes in expression into two components. The first was enriched for neuron-derived transcripts associated with proteostasis including specific members of the molecular chaperone family and was unique to resistant cerebellum. When produced as purified proteins, each of the identified chaperones depressed aggregation of 2N4R tau in vitro at sub-stoichiometric concentrations, consistent with the expression polarity deduced from ratio of ratios testing. In contrast, the second component enriched for glia- and microglia-derived transcripts associated with neuroinflammation, segregating these pathways from susceptibility to tauopathy. These data support the utility of ratio of ratios testing for establishing the polarity of gene expression changes with respect to selective vulnerability. The approach has the potential to identify new targets for drug discovery predicated on their ability to promote resistance to disease in vulnerable neuron populations. Alzheimer’s disease (AD) is defined in part by the appearance of intraneuronal aggregates composed of tau protein. Because their spread through the brain correlates with cognitive decline and neurodegeneration, tau lesions serve as markers for staging disease and for recognizing nerve cell populations differentially vulnerable or resistant to AD pathogenesis. Here we compared a resistant to a vulnerable region of human brain to identify associated molecular signatures and their relationship to risk factors deduced through large-scale human genetics studies. We found that expression of genes associated with protection against intracellular protein misfolding and aggregation accompanied resistance, and that the magnitude of change correlated directly with tau burden appearing in connected brain regions. Resistance also was accompanied by expression changes in two validated AD risk genes that reproduced the directionality reported through genetic analysis. These data support the use of selective vulnerability for interrogating the directionality of gene expression changes in AD and for identifying candidate mediators of resistance to tau pathology.
登录
查看更多内容
影响因子：
14.9
作者：
Dougherty JD;Schmidt EF;Nakajima M;Heintz N
通讯作者：
Heintz N
影响因子：
12.7
作者：
Braak, Heiko;Del Tredici, Kelly
通讯作者：
Del Tredici, Kelly
影响因子：
3.3
作者：
Bussière, T;Gold, G;Hof, PR
通讯作者：
Hof, PR
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.2
作者：
Colangelo, V;Schurr, J;Lukiw, WJ
通讯作者：
Lukiw, WJ