Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome

作者：Nastaran Daneshgar, Mariah Leidinger, Stephanie Le, Marco M. Hefti, Alessandro Prigione, Dao‐Fu Dai · 发表于：Frontiers in Neuroscience · 年份：2023 · DOI：10.3389/fnins.2022.1068498 · 被引用次数：18 · 研究领域：Mitochondrial Function and Pathology、Neuroinflammation and Neurodegeneration Mechanisms、Sphingolipid Metabolism and Signaling

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 ...