Contribution of presenilin/γ-secretase to calsenilin-mediated apoptosis

Dong Gyu Jo, Jae Woong Chang, Hyun Seok Hong, Inhee Mook-Jung, Yong Keun Jung

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Abstract

Mutant presenilins cause early-onset of familial Alzheimer's disease and render cells vulnerable to apoptosis. Calsenilin/DREAM/KChIP3 is a multifunctional calcium-binding protein that interacts with presenilin and mediates calcium-mediated apoptosis. In the present study, we report that the calsenilin-mediated apoptosis is regulated by presenilin. The expression of calsenilin was highly up-regulated in neuronal cells undergoing Aβ42-triggered cell death. The incidence of calsenilin-mediated apoptosis was diminished in presenilin-1-/- mouse embryonic fibroblast cells or neuronal cells stably expressing a loss-of-function presenilin-1 mutant. On the contrary, an array of familial Alzheimer's disease-associated presenilin mutants (gain-of-function) increased calsenilin-induced cell death. Moreover, γ-secretase inhibitors, including compound E and DAPT, decreased the calsenilin-induced cell death. These results suggest that the pro-apoptotic activity of calsenilin coordinates with presenilin/γ-secretase activity to play a crucial role in the neuronal death of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)62-66
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume305
Issue number1
DOIs
StatePublished - May 23 2003

Bibliographical note

Funding Information:
We thank Dr. M. Paul Murphy for the gift of compound E and are grateful to Dr. De Strooper for providing PS1 −/− MEF cell. This work was supported by the grant from National Research Laboratory program (to Y. Jung) and Life Phenomena and Function Research Group Program (2000) of the Korean MOST.

Keywords

  • Alzheimer's disease
  • Calsenilin
  • Cell death
  • Presenilin
  • γ-Secretase

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