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Published online before print January 10, 2008
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From the Department of Cell Biology and Neurosciences,*Osaka University Graduate School of Medicine, Osaka, Japan; the Department of Biochemistry,
Juntendo University School of Medicine, Tokyo, Japan; the Department of Anatomy and Histology,
Fukushima Medical University School of Medicine, Fukushima, Japan; the Department of Neurosurgery,¶Graduate School of Medicine, University of Tokyo, Tokyo, Japan; the Department of Medical Chemistry,**Graduate School of Medicine, Kyoto University, Kyoto, Japan; the Laboratory of Frontier Science,
Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; and Vertex Pharmaceuticals,||Cambridge, Massachusetts
Neonatal hypoxic/ischemic (H/I) brain injury causes neurological impairment, including cognitive and motor dysfunction as well as seizures. However, the molecular mechanisms regulating neuron death after H/I injury are poorly defined and remain controversial. Here we show that Atg7, a gene essential for autophagy induction, is a critical mediator of H/I-induced neuron death. Neonatal mice subjected to H/I injury show dramatically increased autophagosome formation and extensive hippocampal neuron death that is regulated by both caspase-3-dependent and -independent execution. Mice deficient in Atg7 show nearly complete protection from both H/I-induced caspase-3 activation and neuron death indicating that Atg7 is critically positioned upstream of multiple neuronal death executioner pathways. Adult H/I brain injury also produces a significant increase in autophagy, but unlike neonatal H/I, neuron death is almost exclusively caspase-3-independent. These data suggest that autophagy plays an essential role in triggering neuronal death execution after H/I injury and Atg7 represents an attractive therapeutic target for minimizing the neurological deficits associated with H/I brain injury.
This article has been cited by other articles:
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C. T. Chu Eaten Alive: Autophagy and Neuronal Cell Death after Hypoxia-Ischemia Am. J. Pathol., February 1, 2008; 172(2): 284 - 287. [Abstract] [Full Text] [PDF] |
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