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.

PS Dependent APP Cleavage Regulates Glucosylceramide Synthase and is Affected in Alzheimer's Disease

“…The effect found in MEFs expressing the PS-FAD mutations could also be found in vivo , in mouse brains expressing a PS mutation. Beside the effect of PS FAD mutations on GCS expression observed here, for two other PS FAD mutations (PS1 I143T and PS1 G384A) decreased GCS protein stability has been reported [78], further strengthening that ganglioside metabolism is dysregulated in AD.…”

Neutral Glycosphingolipids As Neuroinflammatory Signaling Molecules In Neurodegeneration

“…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 (34). This finding shows a good agreement with a previous work on AD brains.…”

New insights on glucosylated lipids: Metabolism and functions

“…These mutations result in the preferential deposition of pathogenic amyloid β. Interestingly, the UGCG protein expression is reduced in mutant presenilin 1-transfected neuronal cells, but mRNA expression is unaffected [93]. Correspondingly, the amounts of GlcCer and ganglioside, which is synthesized from GlcCer, are significantly decreased in these cells.…”