Daneshgar Nastaran, Leidinger Mariah R, Le Stephanie, Hefti Marco, Prigione Alessandro, Dai Dao-Fu
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Front Neurosci. 2023 Jan 18;16:1068498. doi: 10.3389/fnins.2022.1068498. eCollection 2022.
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.
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。在 Leigh 综合征（LS）患者中，小胶质细胞作为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、Leigh 综合征的小鼠和人类诱导多能干细胞模型进行详细的多方面分析，阐明小胶质细胞在 LS 进展中的作用。我们描述了 3 例 Leigh 综合征患者的脑病理学情况，并对 LS 患者的尸检脑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。利用基因改造的携带 Ndufs4 突变的人类诱导多能干细胞（iPS）衍生神经元和脑类器官，研究 LS 中的神经炎症。我们报告了一项新发现，即在 3 例 Leigh 综合征患者的死后神经病理学检查中，大脑各部位具有活化小胶质细胞特征的 Iba1+细胞显著增加。使用 Leigh 综合征的 Ndufs4 小鼠模型，我们发现从症状发作时开始用培西达替尼部分消融小胶质细胞可改善神经功能并显著延长寿命。Ndufs4 突变的 LS 脑类器官中 NLRP3 和 IL6 促炎途径升高。Ndufs4 突变的 LS iPSC 神经元对谷氨酸兴奋性毒性更敏感，而 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 的 iPSC 模型的研究结果表明，活化的小胶质细胞在 LS 脑病进展中起关键作用。本研究提示在 Leigh 综合征的活动期，小胶质细胞消融和免疫抑制可能具有临床应用潜力。
