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

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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.