Parihar Vipan K, Allen Barrett D, Tran Katherine K, Chmielewski Nicole N, Craver Brianna M, Martirosian Vahan, Morganti Josh M, Rosi Susanna, Vlkolinsky Roman, Acharya Munjal M, Nelson Gregory A, Allen Antiño R, Limoli Charles L
1 Department of Radiation Oncology, University of California, Irvine , Irvine, California.
Antioxid Redox Signal. 2015 Jan 1;22(1):78-91. doi: 10.1089/ars.2014.5929.
Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria.
Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2.
Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology.
Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain.
辐射引起的线粒体功能破坏可加剧氧化应激，并导致代谢紊乱，而这种代谢紊乱被认为会损害中枢神经系统的功能。为阐明线粒体氧化应激在介导辐射对大脑的不良影响中的作用，我们分析了过表达定位于线粒体的人过氧化氢酶的转基因（线粒体过氧化氢酶[MCAT]）小鼠。
与野生型（WT）对照相比，MCAT转基因的过表达显著降低了质子照射后的认知功能障碍。在新物体识别和原地物体识别任务中发现的行为表现显著改善与神经元形态的保留有关。虽然照射后的WT小鼠海马CA1神经元的结构受到显著损害，但MCAT小鼠中的相同神经元并未表现出广泛且显著的辐射诱导的树突复杂性降低。与WT小鼠相比，MCAT小鼠中受照射的神经元保持了树突分支和长度。照射后的MCAT小鼠中受保护的神经元形态也与辐射诱导的长期增强变化的稳定有关。MCAT小鼠中稳定的突触活动与突触AMPA受体亚基GluR1/2组成的改变一致。
我们的研究结果提供了首个证据，表明通过MCAT的过表达可减少与辐射暴露相关的神经认知后遗症，其作用机制涉及神经元形态的保留。
我们的文章记录了通过过氧化氢酶的靶向过表达减少线粒体活性氧的神经保护特性，以及这如何改善质子照射对大脑的不良影响。
