Perineuronal oligodendrocytes protect against neuronal apoptosis through the production of lipocalin-type prostaglandin D synthase in a genetic demyelinating model.
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.
Taniike
Masako
M
Department of Developmental Medicine (Pediatrics), D-5 Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Mohri
Ikuko
I
Eguchi
Naomi
N
Beuckmann
Carsten T
CT
Suzuki
Kinuko
K
Urade
Yoshihiro
Y
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology / Q000473:pathology; D005698:Galactosylceramidase / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054834:Lipocalins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents / Q000378:metabolism; D009836:Oligodendroglia / Q000201:enzymology* / Q000473:pathology; D017354:Point Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation; D015854:Up-Regulation
D054834:Lipocalins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D005698:Galactosylceramidase; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase