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The Journal of Neuroscience, June 15, 2002, 22(12):4885-4896

Perineuronal Oligodendrocytes Protect against Neuronal Apoptosis through the Production of Lipocalin-Type Prostaglandin D Synthase in a Genetic Demyelinating Model

Masako Taniike^{1, *}, Ikuko Mohri^{1, *}, Naomi Eguchi^{2, 3, *}, Carsten T. Beuckmann², Kinuko Suzuki⁴, and Yoshihiro Urade^{2, 3}

¹ Department of Developmental Medicine (Pediatrics), D-5 Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, ² Department of Molecular Behavioral Biology and ³ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Osaka Bioscience Institute, Osaka 565-0874, Japan, and ⁴ Department of Pathology and Laboratory Medicine, and Neuroscience Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7525

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.

Key words: prostaglandin D₂; lipocalin-type prostaglandin D synthase; twitcher; oligodendrocyte; demyelination; galactosylceramidase; apoptosis

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^* M.T., I.M., and N.E. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22124885-12$05.00/0

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