NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
J Inherit Metab Dis. 2024 Nov;47(6):1292-1321. doi: 10.1002/jimd.12804. Epub 2024 Oct 9.
Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.
Leigh 综合征（LS）是一种严重的线粒体疾病，由核或线粒体 DNA 突变引起，导致细胞呼吸和 ATP 产生受损。已经证实超过 100 种基因突变可导致 LS。该疾病最常影响大脑发育和功能，导致认知和运动障碍。由于受影响个体表现出的症状多种多样，且预后存在差异，因此确定其潜在发病机制具有挑战性。为了了解不同 LS 致病突变的疾病机制并找到合适的治疗方法，过去 30 年来已经开发了几种不同的模型系统。本综述总结了 LS 的既定疾病模型及其主要发现。较小的生物体，如酵母，已被用于研究致病突变的生化特性。黑腹果蝇、斑马鱼和秀丽隐杆线虫已被用于剖析 LS 神经和运动症状的病理生理学。包括广泛使用的复合体 I 缺陷 Ndufs4 敲除小鼠模型在内的哺乳动物模型，已被用于研究与疾病相关的发育、认知和运动功能。最后，LS 的细胞模型范围从永生化细胞系和转线粒体细胞杂种到最近的模型系统，如患者来源的诱导多能干细胞（iPSC）。特别是，iPSC 现在允许研究 LS 突变在专门的人类细胞（包括神经元、心肌细胞，甚至三维类器官）中的影响。这些新型模型为基于特定细胞类型中定义的疾病特征开发高通量药物筛选和个性化治疗方法提供了可能性。通过分析所有这些不同的模型系统，本综述旨在提供过去和现在阐明 LS 复杂病理学的方法概述。我们得出结论，每种方法都可以有效地回答关于 LS 的具体研究问题，并且它们的互补使用可能有助于为这种严重且目前无法治疗的疾病找到治疗解决方案。
