Abstract
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a dually functional protein, acting both as a PGD2-synthesizing enzyme and as an extracellular transporter of various lipophilic small molecules. L-PGDS is expressed in oligodendrocytes (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 Krabbe'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. Quantitative RT-PCR revealed that L-PGDS mRNA was up-regulated 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 gangliosides, 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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Gangliosides / classification
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Gangliosides / metabolism*
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Immunohistochemistry / methods
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In Situ Hybridization / methods
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Intracellular Signaling Peptides and Proteins
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / metabolism*
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Intramolecular Oxidoreductases / pharmacokinetics
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Lectins
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Lipocalins
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Lysosomal Storage Diseases / metabolism*
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Lysosomal Storage Diseases / pathology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Biological
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Niemann-Pick C1 Protein
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Oligodendroglia / drug effects
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Oligodendroglia / metabolism*
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Proteins / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Surface Plasmon Resonance / methods
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Time Factors
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Up-Regulation / physiology*
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beta-Galactosidase / deficiency
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beta-N-Acetylhexosaminidases / classification
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beta-N-Acetylhexosaminidases / deficiency
Substances
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Gangliosides
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Intracellular Signaling Peptides and Proteins
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Lectins
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Lipocalins
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Niemann-Pick C1 Protein
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Npc1 protein, mouse
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Proteins
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RNA, Messenger
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beta-Galactosidase
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beta-N-Acetylhexosaminidases
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Intramolecular Oxidoreductases
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prostaglandin R2 D-isomerase