Clues to γ-secretase, huntingtin and Hirano body normal function using the model organism Dictyostelium discoideum.
Clues to γ-secretase, huntingtin and Hirano body normal function using the model organism Dictyostelium discoideum.
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DOI：
10.1186/1423-0127-19-41
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发表时间：
2012-04-10
影响因子：
11
通讯作者：
Myre MA
中科院分区：
文献类型：
--
作者：
Myre MA
许多神经退行性疾病，虽然与它们的大脑功能破坏有关，但表现出显著的细胞和/或区域致病特异性，可能是由于突变蛋白的功能失调所致。然而，神经退行性疾病基因，如Huntingtin(HTT)、ataxins、preenilins(PSEN1/PSEN2)并不是简单地定位于神经元，而是在周围组织中普遍表达；因此，正确理解导致神经元发病的最早诱发事件对于开发有效的长期治疗方法至关重要。这意味着，毫不含糊地说，了解基因的正常功能是至关重要的。不幸的是，许多基因往往是胚胎发生所必需的，这就排除了在整个生物体中研究它们的可能性。对于β-淀粉样前体蛋白(APP)和早老素，导致早发性阿尔茨海默病(AD)的HTT也是如此。为了更好地了解人类的神经系统疾病，已经建立了许多更低和更高的真核细胞模型。因此，问题来了：当所选择的模型不包含神经元时，利用生物体来研究神经疾病有多合理？在这里，我们将回顾模式生物盘基网眼菌作为一种土生阿米巴物种作为研究神经退化基因正常功能的有价值的生物医学工具的惊人和新出现的用途。从历史上看，关于简单生物体对理解细胞病理学病因学的有用性的证据是不可否认的。但使用没有中枢神经系统的有机体来了解大脑疾病呢？我们将首先介绍网柄菌的生活周期，基因组中存在的许多疾病基因，以及它如何提供独特的机会来确定疾病的机制，涉及肌动蛋白病理、线粒体疾病、人类溶酶体和运输障碍以及宿主与病原体的相互作用。其次，我将重点介绍在网柄苔藓中对hTt、早老素γ分泌酶和平野小体功能的最新研究。然后，我将概述利用网盘基菌研究疾病的局限性和未来方向，并最终得出结论，鉴于网柄网柄菌与人类之间基因的进化保守以及生物体的遗传可控性，该系统为发现与神经退化相关的正常基因功能提供了肥沃的环境，并将允许在更高系统中进行翻译研究。
Many neurodegenerative disorders, although related by their destruction of brain function, display remarkable cellular and/or regional pathogenic specificity likely due to a deregulated functionality of the mutant protein. However, neurodegenerative disease genes, for example huntingtin (HTT), the ataxins, the presenilins (PSEN1/PSEN2) are not simply localized to neurons but are ubiquitously expressed throughout peripheral tissues; it is therefore paramount to properly understand the earliest precipitating events leading to neuronal pathogenesis to develop effective long-term therapies. This means, in no unequivocal terms, it is crucial to understand the gene's normal function. Unfortunately, many genes are often essential for embryogenesis which precludes their study in whole organisms. This is true for HTT, the β-amyloid precursor protein (APP) and presenilins, responsible for early onset Alzheimer's disease (AD). To better understand neurological disease in humans, many lower and higher eukaryotic models have been established. So the question arises: how reasonable is the use of organisms to study neurological disorders when the model of choice does not contain neurons? Here we will review the surprising, and novel emerging use of the model organism Dictyostelium discoideum, a species of soil-living amoeba, as a valuable biomedical tool to study the normal function of neurodegenerative genes. Historically, the evidence on the usefulness of simple organisms to understand the etiology of cellular pathology cannot be denied. But using an organism without a central nervous system to understand diseases of the brain? We will first introduce the life cycle of Dictyostelium, the presence of many disease genes in the genome and how it has provided unique opportunities to identify mechanisms of disease involving actin pathologies, mitochondrial disease, human lysosomal and trafficking disorders and host-pathogen interactions. Secondly, I will highlight recent studies on the function of HTT, presenilin γ-secretase and Hirano bodies conducted in Dictyostelium. I will then outline the limitations and future directions in using Dictyostelium to study disease, and finally conclude that given the evolutionary conservation of genes between Dictyostelium and humans and the organisms' genetic tractability, that this system provides a fertile environment for discovering normal gene function related to neurodegeneration and will permit translational studies in higher systems.
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