title: Lipocalin-type prostaglandin D synthase is up-regulated in oligodendrocytes in lysosomal storage diseases and binds gangliosides.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Mohri
authors.forename: Masako
authors.initials: M
authors.lastname: Taniike
authors.forename: Issei
authors.initials: I
authors.lastname: Okazaki
authors.forename: Kuriko
authors.initials: K
authors.lastname: Kagitani-Shimono
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.forename: Takashi
authors.initials: T
authors.lastname: Yagi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takikita
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Kinuko
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005732:Gangliosides / Q000145:classification / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D037102:Lectins; D054834:Lipocalins; D016464:Lysosomal Storage Diseases / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D000077296:Niemann-Pick C1 Protein; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D020349:Surface Plasmon Resonance / Q000379:methods; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology*; D001616:beta-Galactosidase / Q000172:deficiency; D001619:beta-N-Acetylhexosaminidases / Q000145:classification / Q000172:deficiency
chemical_list: D005732:Gangliosides; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D054834:Lipocalins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D001616:beta-Galactosidase; D001619:beta-N-Acetylhexosaminidases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase