科研之友
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摘要
Mutations in the presenilin 1 (PS1) gene are associated with early onset familial Alzheimer%26apos;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 gamma-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.-Mutoh, T., Kawamura, N., Hirabaysshi, Y., Shima, S., Miyashita, T., Ito, S., Asakura, K., Araki, W., Cazzaniga, E., Muto, E., Masserini, M. Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. FASEB J. 26, 3065-3074 (2012). www.fasebj.org
- 出版日期2012-7
