The role of the presenilin-1 homologue gene sel-12 of Caenorhabditis elegans in apoptotic activities.
Many cases of autosomal dominant early onset familial Alzheimer's disease result from mutations in presenilin-1 (PS1). In this study, we examined the role of the PS1 homologue gene sel-12 of Caenorhabditis elegans under oxidative stress and clarified the sel-12-induced apoptosis. A genetic null allele mutant, sel-12(ar171), showed resistance to oxidative stress and prevented mitochondrial dysfunction-induced apoptosis. On the other hand, another allele mutant, sel-12(ar131), that carries a missense mutation showed a proapoptotic activity, which may be the result of a gain of function property. Also, sel-12(ar131)-induced apoptosis was ced-3- and ced-4-dependent. Dantrolene, which specifically inhibits Ca(2+) release from endoplasmic reticulum stores, prevents sel-12(ar131)-induced apoptosis. SEL-12, which is localized in the endoplasmic reticulum, may induce apoptosis through abnormal calcium release from the endoplasmic reticulum. Together, with the previous finding that human PS1 could substitute for SEL-12, these results suggest the similar involvement of PS1-inducing apoptosis under oxidative stress and mitochondrial dysfunction in the Alzheimer's Disease brain.
Kitagawa
Naoyuki
N
Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Shimohama
Shun
S
Oeda
Tomoko
T
Uemura
Kengo
K
Kohno
Ryuichi
R
Kuzuya
Akira
A
Shibasaki
Hiroshi
H
Ishii
Naoaki
N
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015801:Helminth Proteins / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D016296:Mutagenesis; D020125:Mutation, Missense; D018384:Oxidative Stress / Q000235:genetics; D053764:Presenilin-1; D015996:Survival Rate
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D009125:Muscle Relaxants, Central; C508853:PSEN1 protein, human; D053764:Presenilin-1; C095907:SEL-12 protein, C elegans; D003620:Dantrolene; D002118:Calcium