Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha1,4-galactosyltransferase and a mouse model for treating Fabry disease.
Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha1,4-galactosyltransferase and a mouse model for treating Fabry disease.
复制标题
表达人 α1,4-半乳糖基转移酶的转基因小鼠和治疗法布里病的小鼠模型中三酰基神经酰胺水平升高。
DOI：
10.1093/jb/mvq125
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发表时间：
2011
影响因子：
2.7
通讯作者：
Ishii,Satoshi
中科院分区：
文献类型：
--
作者：
Shiozuka,Chikara;Taguchi,Atsumi;Matsuda,Junichiro;Noguchi,Yoko;Kunieda,Takanori;Uchio-Yamada,Kozue;Yoshioka,Hidekatsu;Hamanaka,Ryoji;Yano,Shinji;Yokoyama,Shigeo;Mannen,Kazuaki;Kulkarni,AshokB;Furukawa,Koichi;Ishii,Satoshi
法布里病是一种由α-半乳糖苷酶A（α-Gal A）缺乏引起的溶酶体贮积症，并导致鞘糖脂（主要是神经酰胺三己糖苷（Gb 3））蓄积。在α-Gal A-敲除背景（TgM/KO）中表达人α-Gal A R301 Q突变体的转基因小鼠应可用于研究法布里病的活性位点特异性伴侣（ASSC）疗法。然而，该小鼠心脏组织中的Gb 3含量太低，无法检测到ASSC诱导的效应。为了增加小鼠器官中的Gb 3水平，我们创建了表达人α 1，4-半乳糖基转移酶（Gb 3合酶）的转基因小鼠（TgG 3S）。在TgG 3S小鼠的所有主要器官中观察到高水平的Gb 3。通过将TgG 3S和TgM/KO小鼠杂交制备TgG 3S（+/−）M（+/−）/KO小鼠，TgG 3S（+/−）M（+/−）/KO小鼠心脏中的Gb 3含量为1.4 µg/mg蛋白，高于TgM（+/−）/KO小鼠（<0.1 µg/mg蛋白）。用ASSC（1-脱氧半乳糖野尻霉素）处理可显著诱导α-Gal A活性，并伴随TgG 3S（+/−）M（+/−）/KO小鼠器官中Gb 3含量的降低。这些数据表明，TgG 3S（+/−）M（+/−）/KO小鼠适用于研究法布里病的ASSC疗法，并且TgG 3S小鼠将可用于研究高Gb 3水平对小鼠器官的影响。
Fabry disease is a lysosomal storage disorder caused by an α-galactosidase A (α-Gal A) deficiency and resulting in the accumulation of glycosphingolipids, predominantly globotriaosylceramide (Gb3). A transgenic mouse expressing the human α-Gal A R301Q mutant in an α-Gal A-knockout background (TgM/KO) should be useful for studying active-site-specific chaperone (ASSC) therapy for Fabry disease. However, the Gb3 content in the heart tissue of this mouse was too low to detect an ASSC-induced effect. To increase the Gb3 levels in mouse organs, we created transgenic mice (TgG3S) expressing human α1,4-galactosyltransferase (Gb3 synthase). High levels of Gb3 were observed in all major organs of the TgG3S mouse. A TgG3S (+/−)M(+/−)/KO mouse was prepared by cross-breeding the TgG3S and TgM/KO mice and the Gb3 content in the heart of the TgG3S(+/−)M(+/−)/KO mouse was 1.4 µg/mg protein, higher than in the TgM(+/−)/KO (<0.1 µg/mg protein). Treatment with an ASSC, 1-deoxygalactonojirimycin, caused a marked induction of α-Gal A activity and a concomitant reduction of the Gb3 content in the TgG3S(+/−) M(+/−)/KO mouse organs. These data indicated that the TgG3S(+/−) M(+/−)/KO mouse was suitable for studying ASSC therapy for Fabry disease, and that the TgG3S mouse would be useful for studying the effect of high Gb3 levels in mouse organs.