Lipocalin-type prostaglandin D synthase is up-regulated in oligodendrocytes in lysosomal storage diseases and binds gangliosides

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Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a dually functional protein, acting both as a PGD2-synthes-izing enzyme and as an extracellular transporter of various lipophilic small molecules. L-PGDS is expressed in oligo-dendrocytes (OLs) in the central nervous system and is up-regulated in OLs of the twitcher mouse, a model of globoid cell leukodystrophy (Krabbe's disease). We investigated whether up-regulation of L-PGDS is either unique to Krab-be's disease or is a more generalized phenomenon in lysosomal storage disorders (LSDs), using LSD mouse models of Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis and Niemann-Pick type C1 disease. Quanti-tative RT-PCR revealed that L-PGDS mRNA was up-regu- lated in the brains of all these mouse models. In addition, strong L-PGDS immunoreactivity was observed in OLs, but not in either astrocytes or microglia in these models. Thus, up-regulation of L-PGDS appears to be a common response of OLs in LSDs. Moreover, surface plasmon resonance analyses revealed that L-PGDS binds GM1 and GM2 gan-gliosides, accumulated in neurons in the course of LSD, with high affinities (KD =65 and 210 nM, respectively). This suggests that L-PGDS may play a role in scavenging harmful lipophilic substrates in LSD.

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