Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Department of General Pediatrics, Neonatology and Pediatric Cardiology, Duesseldorf University Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
Nat Commun. 2021 Mar 26;12(1):1929. doi: 10.1038/s41467-021-22117-z.
Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and is currently incurable. The lack of effective models hampers our understanding of the mechanisms underlying the neuronal pathology of LS. Using patient-derived induced pluripotent stem cells and CRISPR/Cas9 engineering, we developed a human model of LS caused by mutations in the complex IV assembly gene SURF1. Single-cell RNA-sequencing and multi-omics analysis revealed compromised neuronal morphogenesis in mutant neural cultures and brain organoids. The defects emerged at the level of neural progenitor cells (NPCs), which retained a glycolytic proliferative state that failed to instruct neuronal morphogenesis. LS NPCs carrying mutations in the complex I gene NDUFS4 recapitulated morphogenesis defects. SURF1 gene augmentation and PGC1A induction via bezafibrate treatment supported the metabolic programming of LS NPCs, leading to restored neuronal morphogenesis. Our findings provide mechanistic insights and suggest potential interventional strategies for a rare mitochondrial disease.
Leigh 综合征（LS）是儿童中线粒体疾病的严重表现形式，目前尚无治愈方法。缺乏有效的模型阻碍了我们对 LS 神经元病理学机制的理解。我们使用患者来源的诱导多能干细胞和 CRISPR/Cas9 工程，开发了一种由 SURF1 基因突变引起的 LS 人类模型。单细胞 RNA 测序和多组学分析显示，突变的神经培养物和脑类器官中的神经元形态发生受损。缺陷出现在神经祖细胞（NPC）水平，这些细胞保持糖酵解增殖状态，无法指导神经元形态发生。携带复合物 I 基因 NDUFS4 突变的 LS NPC 重现了形态发生缺陷。通过 bezafibrate 处理增强 SURF1 基因和诱导 PGC1A，支持 LS NPC 的代谢编程，导致恢复神经元形态发生。我们的研究结果提供了机制见解，并为一种罕见的线粒体疾病提供了潜在的干预策略。
