Characterization of inducible models of Tay-Sachs and related disease.
Characterization of inducible models of Tay-Sachs and related disease.
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DOI：
10.1371/journal.pgen.1002943
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发表时间：
2012-09
期刊：
影响因子：
4.5
通讯作者：
Cachón-González MB
中科院分区：
文献类型：
--
作者：
Sargeant TJ;Drage DJ;Wang S;Apostolakis AA;Cox TM;Cachón-González MB
Tay-Sachs和Sandhoff病是一种先天性的酸性β-N-乙酰氨基己糖苷酶活性缺陷，以神经系统中神经节苷脂GM 2和相关糖缀合物的溶酶体储存为特征。导致不可逆神经元损伤伴神经胶质增生的分子事件尚不清楚;但在神经系统体征明显之前进行基因转移，可有效挽救缺乏β-氨基己糖苷酶A和B的Hex B −/−（Sandhoff）小鼠的急性神经退行性疾病。为了确定治疗效果的决定因素，并建立一个动态的实验平台，系统地研究细胞发病机制的GM 2神经节苷脂沉积症，我们产生了两个诱导的实验模型。由两个启动子（小鼠Hexb和人突触蛋白1启动子）指导的β-氨基己糖苷酶的可逆转基因表达允许Sandhoff小鼠中GM 2神经节苷脂沉积症的进展在预定年龄得到改善。一个单一的自动调节四环素敏感的表达盒控制转基因Hexb在Hexb−/−小鼠大脑中的表达，并提供长期的急性神经元病性疾病的救援，以及伴随的病理性糖缀合物储存和大脑大部分部位的神经胶质增生。最终，发生迟发性脑干和腹侧脊髓病理学，并与肢体张力增加相关。在5周龄小鼠中沉默转基因Hexb表达诱导了Sandhoff病的刻板症状和进展，包括震颤、运动迟缓和后肢瘫痪。与种系Hexb−/−小鼠一样，这些神经退行性表现进展迅速，表明GM 2神经节苷脂沉积症的发病机制和进展不受成熟神经系统发育事件的影响。Sandhoff和Tay-Sachs病是一种毁灭性的神经系统疾病，与婴儿和幼儿的发育退化、失明、癫痫发作和死亡有关。这些疾病是由β-氨基己糖苷酶基因突变引起的，其导致某些脂质、鞘糖脂在神经元溶酶体内的神经元蓄积。目前尚不清楚脂质的积累如何影响神经元功能，尽管基因治疗等有希望的治疗方法正在开发中，但目前还没有临床批准。我们的目标是开发允许随着时间的推移操纵β-氨基己糖苷酶表达的遗传模型。两个诱导型小鼠品系的建立，其中急性桑德霍夫病可以通过在饮食中添加多西环素来“打开”。一旦在成年小鼠中诱发，疾病就会无情地发展，并且显然独立于胎儿和新生儿大脑中发生的快速发育过程，类似于种系Hexb−/−小鼠的疾病过程。这些转基因诱导型桑德霍夫病小鼠品系提供了一个动态平台，用于探索神经元溶酶体β-氨基己糖苷酶活性丧失后立即出现的病理生理学后遗症。
Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid β-N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb−/− (Sandhoff) mice that lack β-hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of β-hexosaminidase directed by two promoters, mouse Hexb and human Synapsin 1 promoters, permitted progression of GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb−/− mice and provided long-term rescue from the acute neuronopathic disorder, as well as the accompanying pathological storage of glycoconjugates and gliosis in most parts of the brain. Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis. As in germline Hexb−/− mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system. Sandhoff and Tay-Sachs disease are devastating neurological diseases associated with developmental regression, blindness, seizures, and death in infants and young children. These disorders are caused by mutations in β-hexosaminidase genes, which result in neuronal accumulation of certain lipids, glycosphingolipids, inside the lysosomes of neurons. It is not yet known how accumulation of lipids affects neuronal function, and although promising treatments such as gene therapy are in development, currently none has been clinically approved. We aimed to develop genetic models that allow manipulation of β-hexosaminidase expression over time. Two inducible strains of mice were created in which acute Sandhoff disease could be “turned on” by the addition of doxycycline in the diet. Once induced in the adult mouse, the disease progressed relentlessly and was apparently independent of the rapid developmental processes that occur in the fetal and neonatal brain, resembling disease course in the germline Hexb−/− mouse. These transgenic inducible strains of Sandhoff disease mice provide a dynamic platform with which to explore the pathophysiological sequelae immediately after loss of neuronal lysosomal β-hexosaminidase activity.
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DOI：
10.1073/pnas.94.2.575
发表时间：
1997-01-21
影响因子：
11.1
作者：
Chung, JH;Bell, AC;Felsenfeld, G
通讯作者：
Felsenfeld, G
影响因子：
14.5
作者：
Crone, C;Petersen, NT;Nielsen, JB
通讯作者：
Nielsen, JB
DOI：
10.1016/j.bbrc.2005.10.054
发表时间：
2005-12-16
影响因子：
3.1
作者：
Miyazaki, S;Miyazaki, T;Miyazaki, J
通讯作者：
Miyazaki, J
影响因子：
3.5
作者：
Mizuguchi, H;Hayakawa, T
通讯作者：
Hayakawa, T
影响因子：
12.4
作者：
Manfredsson, Fredric P.;Burger, Corinna;Mandel, Ronald J.
通讯作者：
Mandel, Ronald J.