title: Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis.
abstract: Mutations in the presenilin 1 (PS1) gene are associated with early onset familial Alzheimer's disease (FAD). In this study, we found that the expression of mutant-PS1 in stable transfectants of SH-SY5Y neuroblastoma cells results in a reduction of the biosynthesis and steady-state levels of glucosylceramide. As an in vivo corroboration of these data, there was a significant reduction of brain glucosylceramide and gangliosides in an animal model of FAD. In mutant-PS1-transfectants (I143T, G384A), immunocytochemistry disclosed a remarkable reduction of glucosylceramide synthase (GlcT-1)-like immunoreactivity in the cells when compared with those of mock- and wild-PS1 transfectants. Immunoprecipitation of GlcT-1 protein from mutant-PS1 transfectants demonstrated a marked reduction in GlcT-1 protein, but there was no reduction in the levels of GlcT-1 mRNA. Both coprecipitation and γ-secretase inhibition experiments suggest that mutant-PS1 seems to form a complex with GlcT-1 protein and to be involved in GlcT-1 degradation, which was never found in other cell types. Thus, mutations in the PS1 gene result in profound glycosphingolipids abnormalities by abnormal molecular interaction with GlcT-1.
authors.affiliation: Department of Neurology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan. tmutoh@fujita-hu.ac.jp
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Mutoh
authors.forename: Naoki
authors.initials: N
authors.lastname: Kawamura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Sayuri
authors.initials: S
authors.lastname: Shima
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Miyashita
authors.forename: Shinji
authors.initials: S
authors.lastname: Ito
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Asakura
authors.forename: Wataru
authors.initials: W
authors.lastname: Araki
authors.forename: Emanuela
authors.initials: E
authors.lastname: Cazzaniga
authors.forename: Eri
authors.initials: E
authors.lastname: Muto
authors.forename: Massimo
authors.initials: M
authors.lastname: Masserini
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D006028:Glycosphingolipids / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D002219:Carbamates; D017931:DNA Primers; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; C410009:L 685458; D050505:Mutant Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D053829:Amyloid Precursor Protein Secretases