title: ABCA2 deficiency results in abnormal sphingolipid metabolism in mouse brain.
abstract: ABCA2, a member of the ATP-binding cassette (ABC) transporter family, is localized mainly to late endosome/lysosomes of oligodendrocytes in brain, but the physiological role and function of ABCA2 are unknown. In this study, we generated mutant mice (ABCA2-null) by targeting the abca2 gene. ABCA2-null mice exhibited a phenotype including lower pregnancy rate and body weight, shorter latency period on the balance beam, and sensitization to environmental stress compared with wild type mice but no abnormality in the cytoarchitectonic and compact myelin structure or oligodendroglial differentiation. Lipid analysis of brain from 11 days to 64 weeks of age revealed significant accumulation of gangliosides along with reduced sphingomyelin (SM) from 4 weeks to 64 weeks of age and accumulation of cerebrosides and sulfatides at 64 weeks of age in ABCA2-null mice compared with wild type mice. In addition, a significant accumulation of the major ganglioside GM1 and reduced SM was detected in the myelin fraction of ABCA2-null brain. Comparison of ABCA2-null and wild type mice revealed weak ABCA2 immunoreactivity in some large pyramidal cells of wild type brain. These results suggest that ABCA2 is involved in the intracellular metabolism of sphingolipids in the brain, particularly SM and gangliosides in oligodendrocytes and certain neurons.
authors.affiliation: Department of Physiology, Akita University School of Medicine, Akita 010-8543, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Sakai
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ban
authors.forename: Katsuya
authors.initials: K
authors.lastname: Yamada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Watanabe
authors.forename: Mayumi
authors.initials: M
authors.lastname: Sasaki
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D005260:Female; D005677:G(M1) Ganglioside / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009186:Myelin Sheath / Q000378:metabolism*; D011247:Pregnancy; D017966:Pyramidal Cells / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; C498824:Abca2 protein, mouse; D013109:Sphingomyelins; D005677:G(M1) Ganglioside