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The investigation of the anti-apoptotic mechanism of lipocalin-type prostaglandin D synthase

脂质运载蛋白型前列腺素D合酶抗凋亡机制的研究

基本信息

批准号：
13670801
负责人：
TANIIKE Masako
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670801/
关键词：
prostaglandin D_2 L-PGDS twitcher oligodendrocyte demyelination HPGDS apoptosis ニューロングリア相関 twitcher

项目摘要

The genetic demyelinating mouse twitcher is a model of the human globoid cell leukodystrophy, caused by galactosylceramidase deficiency. Lipocalin-type prostaglandin (PG) D synthase (L-PGDS), a protein expressed in mature oligodendrocytes(Ols), was progressively upregulated in twitcher Ols; whereas expression of OL-associated proteins 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. 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-posiuve 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. In addition, we disclosed that hematopoietic PGDS (HPGDS), the isozyme of L-PGDS, was also upregulated in activated microglia, accompanied with induced expression of PGD receptor in the neighboring hypertrophic astrocytes. The level of PGD_2 increased ten-fold in the twitcher brains compared with those of normal controls and its level was similarly high in the L-PGDS-deficient twitcher. Taken together, we currently suppose that 1) HPGDS, not LPGDS, is mainly responsible of the production of PGD_2 in the twitcher brains and that 2) the anti-apoptotic effect of L-PGDS is not due to the production of PGD_2 but to its function as a lipocalin.

遗传性脱髓鞘小鼠抽搐是由半乳糖神经酰胺酶缺乏引起的人类球状细胞白质营养不良的模型。脂钙素型前列腺素（PG） D合成酶（L-PGDS）是一种在成熟少突胶质细胞（Ols）中表达的蛋白质，在抽动细胞Ols中逐渐上调；而抽搐脑脱髓鞘过程中ol相关蛋白的表达下调。L-PGDS在神经元周围的表达明显高于束间的表达。在抽动脑纤维束中发现了大量的l - pgds阳性ol，而在抽动脑纤维束中凋亡细胞较少。L-PGDS和GALC双缺陷小鼠除了凋亡的ol数量增加外，还发现了大量的凋亡神经元，这在抽搐的大脑中是从未见过的。在抽动者脑中，双突变体中L-PGDS阳性ol的数量与凋亡核的比例呈线性正相关，提示L-PGDS对细胞凋亡具有剂量依赖性。这些证据表明，L-PGDS是一种抗凋亡分子，可保护抽搐小鼠的神经元和Ols免于凋亡。此外，我们发现造血PGDS (HPGDS)， L-PGDS的同工酶，在活化的小胶质细胞中也上调，并在邻近的肥大星形胶质细胞中诱导PGD受体的表达。与正常对照相比，抽搐患者的PGD_2水平增加了10倍，l - PGD_2缺陷患者的PGD_2水平也同样高。综上所述，我们目前认为：1)在抽搐脑中PGD_2的产生主要是由HPGDS而不是LPGDS负责；2)L-PGDS的抗凋亡作用不是由于PGD_2的产生，而是由于其作为脂质体的功能。