莉氏综合征的疾病模型:从酵母到有机体

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Marie-Thérèse Henke, Alessandro Prigione, Markus Schuelke
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引用次数: 0

摘要

莱氏综合征(LS)是一种严重的线粒体疾病,由核DNA或线粒体DNA突变导致,会损害细胞呼吸和ATP的产生。已有 100 多个基因的突变被证实可导致莱氏综合征。这种疾病最常影响大脑发育和功能,导致认知和运动障碍。由于患者表现出的症状多种多样,预后也不尽相同,因此要确定其发病机制具有挑战性。为了了解不同LS致病突变的发病机制并找到合适的治疗方法,在过去30年中,人们开发了多种不同的模型系统。本综述总结了已建立的LS疾病模型及其主要发现。酵母等小型生物被用来研究致病突变的生化特性。黑腹果蝇、红腹锦鸡和秀丽隐杆线虫被用来剖析LS神经和运动症状的病理生理学。哺乳动物模型,包括广泛使用的复合体 I 缺乏的 Ndufs4 基因敲除小鼠模型,已被用于研究与该疾病相关的发育、认知和运动功能。最后,LS 的细胞模型包括永生细胞系和转线粒体细胞杂交种,以及最新的模型系统,如源自患者的诱导多能干细胞(iPSCs)。特别是,iPSC 现在可以研究 LS 突变对特化人体细胞的影响,包括神经元、心肌细胞甚至三维有机体。后一种模型为开发高通量药物筛选和个性化治疗提供了可能,这些药物筛选和治疗是基于在特定细胞类型背景下捕捉到的特定疾病特征。通过分析所有这些不同的模型系统,本综述旨在概述过去和现在阐明 LS 复杂病理的方法。我们的结论是,每种方法都能有效回答有关 LS 的特定研究问题,它们的互补使用有助于为这种目前无法治疗的严重疾病找到治疗方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disease models of Leigh syndrome: From yeast to organoids.

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.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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