N141I mutant presenilin-2 gene enhances neuronal cell death and decreases bcl-2 expression.
A missense mutation (N1411) in Presenilin-2 (PS-2) gene is associated with early-onset familial Alzheimer's disease. In this study, SK-N-SH human neuroblastoma cells were transfected with wild-type and mutant PS-2 gene to examine presenilin-2 effects on apoptosis. Serum deprivation resulted in enhanced apoptosis in mutant PS-2 comparing with wild-type PS-2. Similarly, mutant PS-2 induced lactate dehydrogenase release to greater extent than wild-type PS-2. Time course experiment demonstrated that the increase in caspase-3-like activity was more pronounced and accelerated in mutant PS-2, compared to wild-type PS-2. While a significant decrease in bcl-2, an anti-apoptotic molecule, occurred in the cells overexpressing mutant PS-2, no significant change was observed in bax, a pro-apoptotic molecule, as compared with the cells overexpressing wild-type PS-2. Our study demonstrated that mutant PS-2 induces apoptosis accompanied by increased caspase-3-like activity and decreased bcl-2 expression in neuronal cells after serum-deprivation.
Mori
Masaki
M
Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan.
Nakagami
Hironori
H
Morishita
Ryuichi
R
Mitsuda
Noriaki
N
Yamamoto
Kei
K
Yoshimura
Shin-ichi
S
Ohkubo
Nobutaka
N
Sato
Naoyuki
N
Ogihara
Toshio
T
Kaneda
Yasufumi
Y
D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D003001:Cloning, Molecular; D016895:Culture Media, Serum-Free; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D019254:Genes, bcl-2 / Q000235:genetics*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008856:Microscopy, Fluorescence; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D053766:Presenilin-2; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D016895:Culture Media, Serum-Free; D018076:DNA, Complementary; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases