Journal
NATURE CHEMICAL BIOLOGY
Volume 1, Issue 2, Pages 112-119Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio711
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Funding
- NIA NIH HHS [R37 AG012859] Funding Source: Medline
- NIGMS NIH HHS [R01 GM64703] Funding Source: Medline
- NINDS NIH HHS [R01 NS37141-08] Funding Source: Medline
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The mechanism of apoptosis has been extensively characterized over the past decade, but little is known about alternative forms of regulated cell death. Although stimulation of the Fas/TNFR receptor family triggers a canonical 'extrinsic' apoptosis pathway, we demonstrated that in the absence of intracellular apoptotic signaling it is capable of activating a common nonapoptotic death pathway, which we term necroptosis. We showed that necroptosis is characterized by necrotic cell death morphology and activation of autophagy. We identified a specific and potent small- molecule inhibitor of necroptosis, necrostatin-1, which blocks a critical step in necroptosis. We demonstrated that necroptosis contributes to delayed mouse ischemic brain injury in vivo through a mechanism distinct from that of apoptosis and offers a new therapeutic target for stroke with an extended window for neuroprotection. Our study identifies a previously undescribed basic cell-death pathway with potentially broad relevance to human pathologies.
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