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Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta
T Nakagawa1, H Zhu, N Morishima
1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease. The family of cysteine proteases, the so- called caspases, are critical mediators of programmed cell death, and thus far 14 family members have been identified. Some of these, such as caspase-8, mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9, mediate apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum (ER) can also result in apoptosis. 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-beta protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity.
Insights
Caspase-12 triggers programmed cell death specifically in the endoplasmic reticulum (ER) due to cellular stress. Mice lacking caspase-12 resist ER stress-induced apoptosis and show reduced neurotoxicity from amyloid-beta.
Area of Science:
- Cell Biology
- Molecular Biology
- Neuroscience
Background:
- Apoptosis (programmed cell death) is vital for development and homeostasis.
- Caspases are key mediators of apoptosis, with 14 identified family members.
- ER stress can induce apoptosis, but the specific mediators were unclear.
Purpose of the Study:
- To investigate the role of caspase-12 in endoplasmic reticulum (ER) stress-induced apoptosis.
- To determine if caspase-12 mediates ER-specific apoptotic pathways.
- To explore caspase-12's involvement in neurotoxicity.
Main Methods:
- Localization studies of caspase-12 within the ER.
- Activation assays for caspase-12 under various stress conditions.
- Analysis of apoptosis in caspase-12 deficient mice and neurons.
Main Results:
- Caspase-12 localizes to the ER and is activated by ER stress (calcium disruption, protein accumulation).
- Caspase-12 is not activated by membrane or mitochondrial apoptotic signals.
- Caspase-12 deficient mice are resistant to ER stress-induced apoptosis.
- Caspase-12 deficient neurons show defective apoptosis in response to amyloid-beta, but not other stimuli.
Conclusions:
- Caspase-12 mediates a specific pathway for apoptosis induction originating from ER stress.
- Caspase-12 plays a role in amyloid-beta-induced neurotoxicity.
- Targeting caspase-12 could be a strategy for neurodegenerative diseases involving ER stress.
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