Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury.
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.
Koike
Masato
M
Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Shibata
Masahiro
M
Tadakoshi
Masao
M
Gotoh
Kunihito
K
Komatsu
Masaaki
M
Waguri
Satoshi
S
Kawahara
Nobutaka
N
Kuida
Keisuke
K
Nagata
Shigekazu
S
Kominami
Eiki
E
Tanaka
Keiji
K
Uchiyama
Yasuo
Y
D000367:Age Factors; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053938:DNA Fragmentation; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology* / Q000503:physiopathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics; D017966:Pyramidal Cells / Q000473:pathology*
C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D053148:Caspase 3; D053179:Caspase 7; D000071193:Autophagy-Related Protein 7