Taniike Masako, Mohri Ikuko, Eguchi Naomi, Beuckmann Carsten T, Suzuki Kinuko, Urade Yoshihiro
Department of Developmental Medicine (Pediatrics), D-5 Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
J Neurosci. 2002 Jun 15;22(12):4885-96. doi: 10.1523/JNEUROSCI.22-12-04885.2002.
The genetic demyelinating mouse "twitcher" is a model of the human globoid cell leukodystrophy, caused by galactosylceramidase (GALC) deficiency. Demyelination in the twitcher brain is secondary to apoptotic death of oligodendrocytes (OLs). Lipocalin-type prostaglandin (PG) D synthase (L-PGDS), a protein expressed in mature OLs, was progressively upregulated in twitcher OLs; whereas expression of OL-associated proteins such as carbonic anhydrase II, myelin basic protein, and myelin-associated glycoprotein was downregulated during demyelination in twitcher brains. The upregulation of L-PGDS was more remarkable in perineuronal OLs than in interfascicular OLs. A larger number of L-PGDS-positive OLs was found in selected fiber tracts of twitcher brains where fewer apoptotic cells were detected. The distribution of L-PGDS-positive OLs was inversely related to the severity of demyelination, as assessed by accumulation of scavenger macrophages. Mice doubly deficient for L-PGDS and GALC disclosed a large number of apoptotic neurons, which were never seen in twitcher brains, in addition to an increased number of apoptotic OLs. A linear positive correlation was observed between the population of L-PGDS-positive OLs in the twitcher brain and the ratio of apoptotic nuclei in the double mutant versus those in the twitcher, suggesting a dose-dependent effect of L-PGDS against apoptosis. These lines of evidence suggest that L-PGDS is an anti-apoptotic molecule protecting neurons and OLs from apoptosis in the twitcher mouse. This is a novel example of OL-neuronal interaction.
遗传性脱髓鞘小鼠“抽搐症小鼠”是人类球状细胞脑白质营养不良的模型,由半乳糖神经酰胺酶(GALC)缺乏引起。抽搐症小鼠大脑中的脱髓鞘继发于少突胶质细胞(OLs)的凋亡死亡。脂质运载蛋白型前列腺素(PG)D合成酶(L-PGDS)是一种在成熟OLs中表达的蛋白质,在抽搐症小鼠的OLs中逐渐上调;而在抽搐症小鼠大脑脱髓鞘过程中,与OL相关的蛋白质如碳酸酐酶II、髓鞘碱性蛋白和髓鞘相关糖蛋白的表达则下调。L-PGDS在神经元周围的OLs中的上调比在束间OLs中更显著。在抽搐症小鼠大脑的选定纤维束中发现了大量L-PGDS阳性的OLs,而在这些区域检测到的凋亡细胞较少。通过清道夫巨噬细胞的积累评估,L-PGDS阳性OLs的分布与脱髓鞘的严重程度呈负相关。L-PGDS和GALC双缺陷的小鼠除了凋亡OLs数量增加外,还出现了大量凋亡神经元,这在抽搐症小鼠大脑中从未见过。在抽搐症小鼠大脑中L-PGDS阳性OLs的数量与双突变体与抽搐症小鼠中凋亡细胞核的比例之间观察到线性正相关,表明L-PGDS对凋亡具有剂量依赖性作用。这些证据表明,L-PGDS是一种抗凋亡分子,可保护抽搐症小鼠中的神经元和OLs免受凋亡。这是OL-神经元相互作用的一个新例子。