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

Research output: Contribution to journalArticle

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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

Fingerprint

Presenilin-1
Glycosphingolipids
Biosynthesis
Glucosylceramides
Alzheimer Disease
ceramide glucosyltransferase
Genes
Amyloid Precursor Protein Secretases
Mutation
Molecular interactions
Gangliosides
Mutant Proteins
Coprecipitation
Neuroblastoma
Immunoprecipitation
Brain
Animals
Proteins
Animal Models
Immunohistochemistry

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., ... 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
Mutoh, Tatsuro ; Kawamura, Naoki ; Hirabayashi, Yoshio ; Shima, Sayuri ; Miyashita, Tadayuki ; Ito, Shinji ; Asakura, Kunihiko ; Araki, Wataru ; Cazzaniga, Emanuela ; Muto, Eri ; Masserini, Massimo. / Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. In: FASEB Journal. 2012 ; Vol. 26, No. 7. pp. 3065-3074.
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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, vol. 26, no. 7, pp. 3065-3074. https://doi.org/10.1096/fj.11-198630

Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. / Mutoh, Tatsuro; Kawamura, Naoki; Hirabayashi, Yoshio; Shima, Sayuri; Miyashita, Tadayuki; Ito, Shinji; Asakura, Kunihiko; Araki, Wataru; Cazzaniga, Emanuela; Muto, Eri; Masserini, Massimo.

In: FASEB Journal, Vol. 26, No. 7, 01.07.2012, p. 3065-3074.

Research output: Contribution to journalArticle

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T1 - Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis

AU - Mutoh, Tatsuro

AU - Kawamura, Naoki

AU - Hirabayashi, Yoshio

AU - Shima, Sayuri

AU - Miyashita, Tadayuki

AU - Ito, Shinji

AU - Asakura, Kunihiko

AU - Araki, Wataru

AU - Cazzaniga, Emanuela

AU - Muto, Eri

AU - Masserini, Massimo

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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.

AB - 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.

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