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Posttranslational Modulation and Proteolysis

開催日 2014/9/13
時間 14:00 - 15:00
会場 Poster / Exhibition(Event Hall B)

Hippocampal pyramidal neurons lacking LC3A and LC3B are resistant to hypoxic-ischemic brain injury in neonatal mice

  • P3-046
  • 山口 隼司 / Junji Yamaguchi:1 砂堀 毅彦 / Sunabori Takehiko:2 小池 正人 / Koike Masato:2 七尾 友久 / Nanao Tomohisa:1 柴田 昌宏 / Shibata Masahiro:3 内山 安男 / Uchiyama Yasuo:1 
  • 1:順天堂大学大学院医学研究科 神経疾患病態構造学 / Dept. Cell & Mol. Neuropathol., Juntendo Univ Sch. Med., Tokyo, Japan 2:順天堂大学大学院医学研究科 神経生物学・形態学講座 / Dept. Cell Biol & Neurosci., Juntendo Univ. Sch. Med., Tokyo, Japan 3:新潟大学医学部医学科 生体機能調節医学専攻機能再建医学大講座肉眼解剖学 / Dept. Gross Anat & Morphogene, Niigata Univ. Sch. Med & Dent Sci., Niigata, Japan 

Although LC3, a mouse homologue of yeast Atg8, has mainly been used for a marker protein of autophagy, little is known about roles of subtypes of LC3, LC3A and LC3B, or whether these proteins compensate their roles for each other during autophagic processes. For this, we produced LC3A and LC3B (LC3A/B)-double deficient (KO) mice, which were born normally and were grown-up to be capable of reproduction. Using these KO mice, both mRNA and protein levels of LC3 homologous proteins, a GABARAP family of proteins, were examined in brain and other tissues and found that they did not significantly alter between wild-type and LC3A/B-double deficient mice, although the expression level of GABARAP only was significantly higher in liver tissue than in brain tissue. These results indicate that basic autophagy may work normally in neurons of LC3A/B-deficient brains. Since we have previously shown that Atg7-deficiency rescues mouse neonatal hippocampal pyramidal neurons from hypoxic-ischemic injury (H/I), LC3A/B-double deficient mice were applied to this H/I model. As previously reported, hippocampal pyramidal neurons in wild-type mice were vulnerable to H/I injury, while the protein amount of LC3-II was markedly elevated from 9 to 24 hours after H/I injury. In contrast, hippocampal pyramidal neurons deficient in LC3A/B were resistant to the H/I injury. These results suggest that LC3A/B, but not GABARAP family of proteins, are involved in H/I injury-mediated pyramidal neuron death that occurs in the hippocampal pyramidal layers of neonatal mouse brains. As shown in our previous study, excess autophagic stress may induce neuron death. Our present data using LC3A/B-deficient mice strongly support the presence of H/I injury-mediated autophagic neuron death in neonatal brains. Of course, further study is required to elucidate the molecular mechanism of why H/I injury-mediated neuron death is suppressed by deficiency in Atg7 or LC3A/B.

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