C9orf72 suppresses systemic and neural inflammation induced by gut bacteria
C9orf72 suppresses systemic and neural inflammation induced by gut bacteria
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DOI：
10.1038/s41586-020-2288-7
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发表时间：
2020-05-13
期刊：
影响因子：
64.8
通讯作者：
Eggan, Kevin
中科院分区：
文献类型：
--
作者：
Burberry, Aaron;Wells, Michael F.;Eggan, Kevin
C9ORF72 中的六核苷酸重复扩增是导致肌萎缩侧索硬化症和额颞叶痴呆的最常见遗传变异(1,2)。 C9ORF72 突变通过功能获得和功能丧失机制发挥作用，诱导与神经变性有关的通路(3-9)。该扩展被转录为长重复 RNA，在其非规范翻译为神经毒性二肽蛋白 (3,4) 之前，它会负隔离 RNA 结合蛋白 (5)。 RNA 聚合酶无法读取突变也会降低内源性 C9ORF72 基因产物的丰度，该基因产物在内溶酶体途径中发挥作用并抑制全身和神经炎症 (6-9)。值得注意的是，重复扩张的影响在肌萎缩侧索硬化症或额颞叶痴呆高患病率的家庭中具有不完全外显率，这表明遗传或环境因素会改变每个人的疾病风险。确定疾病调节因素具有相当大的转化意义，因为它可以提出降低发展为肌萎缩侧索硬化症或额颞叶痴呆的风险或减缓进展的策略。在这里，我们报告说，免疫刺激细菌 (10,11) 丰度减少的环境可以保护 C9orf72 突变小鼠免于过早死亡，并显着改善其潜在的全身炎症和自身免疫。与 C9orf72 防止微生物群诱导病理性炎症反应的功能一致，我们发现使用广谱抗生素减少突变小鼠的微生物负荷，以及从保护性环境中移植肠道微生物群，可以减轻炎症表型，即使在炎症表型发作后也是如此。我们的研究提供了进一步的证据，表明我们肠道的微生物组成对大脑健康具有重要作用，并且可以以令人惊讶的方式与众所周知的神经系统疾病遗传风险因素相互作用。免疫刺激性肠道细菌丰度的减少改善了带有 C9orf72 突变的小鼠的炎症和自身免疫表型，而在人类直系同源物中，这种突变与肌萎缩侧索硬化症和额颞叶痴呆有关。
A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia(1,2). The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration(3-9). The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins(5) before its non-canonical translation into neural-toxic dipeptide proteins(3,4). The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation(6-9). Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria(10,11) protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.Reduced abundance of immune-stimulating gut bacteria ameliorated the inflammatory and autoimmune phenotypes of mice with mutations in C9orf72, which in the human orthologue are linked to amyotrophic lateral sclerosis and frontotemporal dementia.