Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome.
Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome.
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DOI：
10.3389/fnins.2022.1068498
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发表时间：
2022
影响因子：
4.3
通讯作者：
Dai, Dao-Fu
中科院分区：
文献类型：
--
作者：
Daneshgar, Nastaran;Leidinger, Mariah R. R.;Le, Stephanie;Hefti, Marco;Prigione, Alessandro;Dai, Dao-Fu
神经炎症是导致神经退行性疾病中神经元死亡和功能障碍的主要机制之一。小胶质细胞作为 Leigh 综合征 (LS) 患者炎症主要介质的作用尚不清楚。本研究旨在通过对 LS 神经病理学、小鼠和人类 Leigh 综合征诱导多能干细胞模型的详细多管齐下分析，阐明小胶质细胞在 LS 进展中的作用。我们描述了三例 Leigh 综合征病例的脑病理学，并对 LS 患者尸检脑部进行了免疫组织化学染色。我们使用 LS (Ndufs4−/−) 小鼠模型，通过药理学方法研究小胶质细胞部分消融的效果。使用转基因人类诱导多能干细胞 (iPS) 衍生的神经元和具有 Ndufs4 突变的脑类器官来研究 LS 的神经炎症。我们报告了一项新的观察结果：在三名 Leigh 综合征患者的死后神经病理学检查中，大脑各个部位的具有激活小胶质细胞特征的 Iba1+ 细胞显着增加。使用 Leigh 综合征的 Ndufs4−/− 小鼠模型，我们发现在症状出现时使用 Pexidartinib 部分消融小胶质细胞可改善神经功能并显着延长寿命。 Ndufs4 突变 LS 脑类器官的 NLRP3 和 IL6 促炎症通路升高。 Ndufs4 突变的 LS iPSC 神经元更容易受到谷氨酸兴奋性毒性的影响，IL-6 进一步增强了这种毒性。我们对 LS 人脑病理学、Ndufs4 缺陷小鼠和 LS iPSC 模型的研究结果表明，激活的小胶质细胞在 LS 脑病的进展中发挥着关键作用。这项研究表明小胶质细胞消融和免疫抑制在 Leigh 综合征活跃期具有潜在的临床应用价值。
Neuroinflammation is one of the main mechanisms leading to neuronal death and dysfunction in neurodegenerative diseases. The role of microglia as primary mediators of inflammation is unclear in Leigh syndrome (LS) patients. This study aims to elucidate the role of microglia in LS progression by a detailed multipronged analysis of LS neuropathology, mouse and human induced pluripotent stem cells models of Leigh syndrome. We described brain pathology in three cases of Leigh syndrome and performed immunohistochemical staining of autopsy brain of LS patients. We used mouse model of LS (Ndufs4−/−) to study the effect of microglial partial ablation using pharmacologic approach. Genetically modified human induced pluripotent stem cell (iPS) derived neurons and brain organoid with Ndufs4 mutation were used to investigate the neuroinflammation in LS. We reported a novel observation of marked increased in Iba1+ cells with features of activated microglia, in various parts of brain in postmortem neuropathological examinations of three Leigh syndrome patients. Using an Ndufs4−/− mouse model for Leigh syndrome, we showed that partial ablation of microglia by Pexidartinib initiated at the symptom onset improved neurological function and significantly extended lifespan. Ndufs4 mutant LS brain organoid had elevated NLRP3 and IL6 pro-inflammatory pathways. Ndufs4-mutant LS iPSC neurons were more susceptible to glutamate excitotoxicity, which was further potentiated by IL-6. Our findings of LS human brain pathology, Ndufs4-deficient mouse and iPSC models of LS suggest a critical role of activated microglia in the progression of LS encephalopathy. This study suggests a potential clinical application of microglial ablation and immunosuppression during the active phase of Leigh syndrome.
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影响因子：
25
作者：
Ueno, Masaki;Fujita, Yuki;Yamashita, Toshihide
通讯作者：
Yamashita, Toshihide
影响因子：
56.9
作者：
Nimmerjahn, A;Kirchhoff, F;Helmchen, F
通讯作者：
Helmchen, F
DOI：
10.1073/pnas.1006214107
发表时间：
2010-06-15
影响因子：
11.1
作者：
Quintana, Albert;Kruse, Shane E.;Palmiter, Richard D.
通讯作者：
Palmiter, Richard D.
影响因子：
11
作者：
Hopperton KE;Mohammad D;Trépanier MO;Giuliano V;Bazinet RP
通讯作者：
Bazinet RP
影响因子：
4.3
作者：
Dai DF;Danoviz ME;Wiczer B;Laflamme MA;Tian R
通讯作者：
Tian R