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

研究成果: Article査読

8 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)3065-3074
ページ数10
ジャーナルFASEB Journal
26
7
DOI
出版ステータスPublished - 01-07-2012

All Science Journal Classification (ASJC) codes

  • バイオテクノロジー
  • 生化学
  • 分子生物学
  • 遺伝学

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