title: Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity.
abstract: 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.
authors.affiliation: Institute of Neurosciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Mi
authors.forename: B
authors.initials: B
authors.lastname: Hou
authors.forename: Q-M
authors.initials: QM
authors.lastname: Liao
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.forename: Q
authors.initials: Q
authors.lastname: Luo
authors.forename: Y-K
authors.initials: YK
authors.lastname: Dai
authors.forename: G
authors.initials: G
authors.lastname: Ju
authors.forename: W-L
authors.initials: WL
authors.lastname: Jin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000070798:Nogo Proteins; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D009185:Myelin Proteins; D000070798:Nogo Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000603197:Rtn4 protein, rat; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D048049:Extracellular Signal-Regulated MAP Kinases