Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice.
Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice.
复制标题
神经功能缺陷和糖脂果脂脂累积的糖脂B缺乏小鼠。
DOI：
10.1093/hmg/ddn135
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发表时间：
2008-08-01
影响因子：
3.5
通讯作者：
Grabowski, Gregory A.
中科院分区：
文献类型：
--
作者：
Sun, Ying;Witte, David P.;Ran, Huimin;Zamzow, Matt;Barnes, Sonya;Cheng, Hua;Han, Xianlin;Williams, Michael T.;Skelton, Matthew R.;Vorhees, Charles V.;Grabowski, Gregory A.
Saposin B 衍生自多功能前体 Prosaposin，可作为多种鞘糖脂 (GSL) 水解酶的活性增强剂。人类中存在皂苷 B 突变，其表型类似于异染性脑白质营养不良。为了深入了解 saposin B 的生理功能，通过对 prosaposin 基因座的外显子 7 中的必需半胱氨酸进行敲入突变，在小鼠中产生了特定的缺陷。在纯合子 (B−/−) 小鼠中未检测到 saposin B 蛋白，而 proaposin、saposin A、C 和 D 处于正常水平。 B−/− 小鼠在 15 个月时表现出缓慢进行性的神经运动恶化和轻微的头部震颤。大脑和肾脏中存在过量的羟基和非羟基脂肪酸硫苷脂水平。在大脑、脊髓和肾脏中发现了阿新蓝阳性（硫苷脂）储存细胞。超微结构分析显示肾脏、坐骨神经、大脑和脊髓组织中存在层状包涵体物质。 B−/− 小鼠各组织中的乳糖神经酰胺 (LacCer) 和三酰神经酰胺 (TriCer) 增加，支持了 saposin B 在这些脂质降解中的体内作用。 B−/− 小鼠大脑中 CD68 阳性小胶质细胞和激活的 GFAP 阳性星形胶质细胞显示出促炎反应。这些发现描述了 saposin B 在体内降解几种 GSL 中的作用及其在维持 CNS 功能中的主要功能。 B−/− 为理解这种皂苷对 GSL 代谢和稳态的贡献提供了一个有用的模型。
Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific deficiency was created in mice by a knock-in mutation of an essential cysteine in exon 7 of the prosaposin locus. No saposin B protein was detected in the homozygotes (B−/−) mice, whereas prosaposin, and saposins A, C and D were at normal levels. B−/− mice exhibited slowly progressive neuromotor deterioration and minor head tremor by 15 months. Excess hydroxy and non-hydroxy fatty acid sulfatide levels were present in brain and kidney. Alcian blue positive (sulfatide) storage cells were found in the brain, spinal cord and kidney. Ultrastructural analyses showed lamellar inclusion material in the kidney, sciatic nerve, brain and spinal cord tissues. Lactosylceramide (LacCer) and globotriaosylceramide (TriCer) were increased in various tissues of B−/− mice supporting the in vivo role of saposin B in the degradation of these lipids. CD68 positive microglial cells and activated GFAP positive astrocytes showed a proinflammatory response in the brains of B−/− mice. These findings delineate the roles of saposin B for the in vivo degradation of several GSLs and its primary function in maintenance of CNS function. B−/− provide a useful model for understanding the contributions of this saposin to GSL metabolism and homeostasis.
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影响因子：
6.5
作者：
Ciaffoni, Fiorella;Tatti, Massimo;Vaccaro, Anna Maria
通讯作者：
Vaccaro, Anna Maria
DOI：
10.1073/pnas.93.25.14821
发表时间：
1996-12-10
影响因子：
11.1
作者：
Hess, B;Saftig, P;Gieselmann, V
通讯作者：
Gieselmann, V
影响因子：
3.9
作者：
Hiraiwa, M;Martin, BM;OBrien, JS
通讯作者：
OBrien, JS
影响因子：
2.9
作者：
Jiang, Xuntian;Cheng, Hua;Han, Xianlin
通讯作者：
Han, Xianlin
DOI：
10.1073/pnas.94.6.2540
发表时间：
1997-03-18
影响因子：
11.1
作者：
Ohshima, T;Murray, GJ;Kulkarni, AB
通讯作者：
Kulkarni, AB