Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity
Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity
复制标题
Amino-Nogo-A 拮抗活性氧的产生并保护未成熟的初级皮质神经元免受氧化毒性
DOI：
10.1038/cdd.2011.206
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发表时间：
2012-07-01
影响因子：
12.4
通讯作者：
Jin, W-L
中科院分区：
文献类型：
--
作者：
Mi, Y-J;Hou, B.;Jin, W-L
Nogo-A最初被鉴定为CNS髓鞘轴突再生的抑制剂。Nogo-A主要由少突胶质细胞表达，也由一些神经元亚群表达，特别是在发育中的神经系统中。尽管广泛的研究已经揭示了Nogo-A在神经突生长抑制、前体迁移、神经元稳态、可塑性和神经变性中的调节作用，但其在神经元中的细胞自主功能在很大程度上是未知的。在这里，我们表明，HIV-1的反式激活介导的氨基Nogo-A蛋白转导到培养的原代皮层神经元实现了几乎完全的神经保护对外源性过氧化氢（H2 O2）诱导的氧化应激。内源性表达的神经元Nogo-A在H2 O2处理后显著下调。此外，敲低Nogo-A导致对急性氧化损伤的更敏感性，并显著增加神经元死亡。氨基-Nogo-A与过氧化物氧还蛋白2（Prdx 2）相互作用，减少活性氧（ROS）的产生和细胞外信号调节激酶磷酸化，发挥神经保护作用。结构-功能作图实验表明，在NiG-Δ20中，包含氨基-Nogo-A的残基290-562的新区域对于防止氧化性神经元死亡是必不可少的。此外，突变分析证实，半胱氨酸残基424，464和559参与抑制ROS的产生和amino-Nogo-A的神经保护作用。我们的数据表明，神经元Nogo-A可能通过与Prdx 2相互作用和清除ROS，在改善神经元抗氧化损伤的存活中发挥细胞自主作用。
Nogo-A is originally identified as an inhibitor of axon regeneration from the CNS myelin. Nogo-A is mainly expressed by oligodendrocytes, and also by some neuronal subpopulations, particularly in the developing nervous system. Although extensive studies have uncovered regulatory roles of Nogo-A in neurite outgrowth inhibition, precursor migration, neuronal homeostasis, plasticity and neurodegeneration, its cell-autonomous functions in neurons are largely uncharacterized. Here, we show that HIV-1 trans-activating-mediated amino-Nogo-A protein transduction into cultured primary cortical neurons achieves an almost complete neuroprotection against oxidative stress induced by exogenous hydrogen peroxide (H 2 O 2). Endogenously expressed neuronal Nogo-A is significantly downregulated upon H 2 O 2 treatment. Furthermore, knockdown of Nogo-A results in more susceptibility to acute oxidative insults and markedly increases neuronal death. Interacting with peroxiredoxin 2 (Prdx2), amino-Nogo-A reduces reactive oxygen species (ROS) generation and extracellular signal-regulated kinase phosphorylation to exert neuroprotective effects. Structure–function mapping experiments reveal that, out of NiG-Δ20, a novel region comprising residues 290–562 of amino-Nogo-A is indispensable for preventing oxidative neuronal death. Moreover, mutagenesis analysis confirms that cysteine residues 424, 464 and 559 are involved in the inhibition of ROS generation and neuroprotective role of amino-Nogo-A. Our data suggest that neuronal Nogo-A might play a cell-autonomous role in improving neuronal survival against oxidative insult through interacting with Prdx2 and scavenging of ROS.