Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice
Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice
复制标题
DOI：
10.1073/pnas.251485198
复制
发表时间：
2001-11-20
影响因子：
11.1
通讯作者：
Hofmann, SL
中科院分区：
文献类型：
--
作者：
Gupta, P;Soyombo, AA;Hofmann, SL
PPT1和PPT2编码两种催化长链脂肪酰辅酶A水解的溶酶体硫酯酶。除了此功能外，PPT1（棕榈酰蛋白硫酯酶 1）还可水解在溶酶体中降解的蛋白质中修饰的半胱氨酸残基中的脂肪酸。人类 PPT1 缺乏症会导致神经退行性疾病，即婴儿神经元蜡质脂褐质沉着症（也称为婴儿巴顿病）。在当前的工作中，我们对 PPT1 和 PPT2 基因进行了工程破坏，以创造出缺乏任何一种酶的“基因敲除”小鼠。两个品系的小鼠均能存活并具有生育能力。然而，这两个品系分别在中位年龄 21 周和 29 周时出现痉挛（“紧握”表型）。 PPT1 基因敲除小鼠的运动异常进展，导致 10 个月龄时死亡。相比之下，大多数 PPT2 小鼠在 12 个月时仍存活。 PPT1 小鼠的肌阵挛性抽搐和癫痫发作很明显。自发荧光存储材料在两种小鼠的大脑中都很引人注目。神经元丢失和细胞凋亡在 PPT1 缺陷的大脑中尤为突出。这些研究提供了婴儿神经元蜡样质脂褐质沉积症的小鼠模型，并进一步表明 PPT2 在大脑中发挥着 PPT1 所没有的作用。
PPT1 and PPT2 encode two lysosomal thioesterases that catalyze the hydrolysis of long chain fatty acyl CoAs. In addition to this function, PPT1 (palmitoyl-protein thioesterase 1) hydrolyzes fatty acids from modified cysteine residues in proteins that are undergoing degradation in the lysosome. PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis (also known as infantile Batten disease). in the current work, we engineered disruptions in the PPT1 and PPT2 genes to create "knockout" mice that were deficient in either enzyme. Both lines of mice were viable and fertile. However, both lines developed spasticity (a "clasping" phenotype) at a median age of 21 wk and 29 wk, respectively. Motor abnormalities progressed in the PPT1 knockout mice, leading to death by 10 mo of age. In contrast, the majority of PPT2 mice were alive at 12 mo. Myoclonic jerking and seizures were prominent in the PPT1 mice. Autofluorescent storage material was striking throughout the brains of both strains of mice. Neuronal loss and apoptosis were particularly prominent in PPT1-deficient brains. These studies provide a mouse model for infantile neuronal ceroid lipofuscinosis and further suggest that PPT2 serves a role in the brain that is not carried out by PPT1.