Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis

Tatsuro Mutoh, Naoki Kawamura, Yoshio Hirabayashi, Sayuri Shima, Tadayuki Miyashita, Shinji Ito, Kunihiko Asakura, Wataru Araki, Emanuela Cazzaniga, Eri Muto, Massimo Masserini

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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.

Original languageEnglish
Pages (from-to)3065-3074
Number of pages10
JournalFASEB Journal
Volume26
Issue number7
DOIs
Publication statusPublished - 01-07-2012

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All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Mutoh, T., Kawamura, N., Hirabayashi, Y., Shima, S., Miyashita, T., Ito, S., Asakura, K., Araki, W., Cazzaniga, E., Muto, E., & Masserini, M. (2012). Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. FASEB Journal, 26(7), 3065-3074. https://doi.org/10.1096/fj.11-198630