Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β

Toshiyuki Nakagawa, Hong Zhu, Nobuhiro Morishima, En Li, Jin Xu, Bruce A. Yankner and Junying Yuan ()
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Toshiyuki Nakagawa: Harvard Medical School
Hong Zhu: Harvard Medical School
Nobuhiro Morishima: Biodesign Research Group, RIKEN (the Institute of Physical and Chemical Research)
En Li: Cardiovascular Research Center, Massachusetts General Hospital
Jin Xu: Harvard Medical School and Children's Hospital, Enders 260
Bruce A. Yankner: Harvard Medical School and Children's Hospital, Enders 260
Junying Yuan: Harvard Medical School

Nature, 2000, vol. 403, issue 6765, 98-103

Abstract: Abstract Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease1,2. The family of cysteine proteases, the so-called caspases, are critical mediators of programmed cell death3, and thus far 14 family members have been identified. Some of these, such as caspase-8 (refs 4, 5), mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9 (ref. 6), mediate apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum (ER) can also result in apoptosis7. Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals. Mice that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli. Furthermore, we show that caspase-12-deficient cortical neurons are defective in apoptosis induced by amyloid-β protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-β neurotoxicity.

Date: 2000
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DOI: 10.1038/47513

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