The role of the presenilin-1 homologue gene sel-12 of Caenorhabditis elegans in apoptotic activities |
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Authors: | Kitagawa Naoyuki Shimohama Shun Oeda Tomoko Uemura Kengo Kohno Ryuichi Kuzuya Akira Shibasaki Hiroshi Ishii Naoaki |
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Affiliation: | Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. |
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Abstract: | 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. |
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