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

Abstract

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.

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

“…5 A, B, and D). Tubulovesicular structures, which have been described in various pathological conditions and are believed to represent a stage of axonal degeneration (18), were observed in the cerebellar axons (Fig. 5B).…”

Prostaglandin D2Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

“…In the normal CNS, L-PGDS is expressed in oligodendroglia , and HPGDS in microglia (Mohri et al, 2003). We found previously that both L-PGDS (Taniike et al, 2002) and HPGDS (Mohri et al, 2006) were upregulated together with specific elevation of PGD 2 in the brains of twitcher mice, a model of chronic neuroinflammation. Suppression of HPGDS-PGD 2 -DP 1 signaling resulted in the clinicopathological improvement in twitcher (Mohri et al, 2006).…”

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

“…One of the features of EAE/MS is demyelination, which coincides with oligodendrocyte cell death. L-PGDS is thought to be an anti-apoptotic molecule that protects oligodendrocytes, because the oligodendrocyte apoptosis was enhanced in the brain of L-PGDS-deficient twitcher mice (39). In human MS, L-PGDS expression was increased especially in the remyelinated lesions (40).…”