Contribution of presenilin/gamma-secretase to calsenilin-mediated apoptosis.
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 Abeta42-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, gamma-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/gamma-secretase activity to play a crucial role in the neuronal death of Alzheimer's disease.
Department of Life Science, Kwangju Institute of Science and Technology, Kwangju 500-712, Republic of Korea.
Dong-Gyu
DG
Jo
Jae-Woong
JW
Chang
Hyun-Seok
HS
Hong
Inhee
I
Mook-Jung
Yong-Keun
YK
Jung
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D010450:Endopeptidases / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051605:Kv Channel-Interacting Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D053764:Presenilin-1; D051381:Rats; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; C496756:Csen protein, mouse; C496749:KCNIP3 protein, human; C496760:Kcnip3 protein, rat; D051605:Kv Channel-Interacting Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012097:Repressor Proteins; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse