Loss of DJ-1 elicits retinal abnormalities, visual dysfunction, and increased oxidative stress in mice.
Loss of DJ-1 elicits retinal abnormalities, visual dysfunction, and increased oxidative stress in mice.
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DOI：
10.1016/j.exer.2015.07.014
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发表时间：
2015-10
影响因子：
3.4
通讯作者：
Shadrach KG
中科院分区：
文献类型：
--
作者：
Bonilha VL;Bell BA;Rayborn ME;Yang X;Kaul C;Grossman GH;Samuels IS;Hollyfield JG;Xie C;Cai H;Shadrach KG
DJ-1/Park7突变或缺失可导致常染色体隐性遗传性早发性帕金森病(PD)。因此，DJ-1蛋白在脑和神经元中得到了广泛的研究。帕金森病患者表现出视觉症状；然而，携带DJ-1/Park7突变的帕金森病患者的视觉症状尚不清楚。在这项研究中，我们分析了3个月和6个月大的DJ-1基因敲除(KO)小鼠的视网膜结构和生理，以确定DJ-1功能丧失如何特异性地影响PD患者的表型。与对照组相比，DJ-1KO组小鼠暗适应ERG b波和视锥ERG的波幅增加，而DC-ERG部分成分的波幅降低。DJ-1KO视网膜主要结构改变位于外丛状层(OPL)、光感受器和视网膜色素上皮(RPE)，3个月时观察到，6个月时逐渐增多。DJ-1KO小鼠视网膜RPE变薄，OPL内结构发生改变。DJ-1 KO视网膜外节排列紊乱，红/绿视锥视蛋白染色中央减少，Ezrin标记减少，核眼标记分布更广，多巴胺能神经元酪氨酸羟化酶减少，7，8-二氢-8-氧鸟嘌呤标记的DNA氧化增加。DJ-1KO小鼠在单次尾静脉注射NaIO3引起选择性氧化损伤后观察到加速的视网膜外萎缩，暴露出对氧化应激的易感性增加。我们的数据表明，DJ-1缺乏的视网膜表现出与氧化应激增加相关的形态异常和生理功能障碍的迹象。与氧化应激相关的RPE细胞变性是老年性黄斑变性(AMD)的一个重要标志。因此，除了详细描述由于缺乏DJ-1而导致的视觉缺陷外，我们的数据还与AMD的发病机制有关。
DJ-1/PARK7 mutations or deletions cause autosomal recessive early onset Parkinson’s disease (PD). Thus, DJ-1 protein has been extensively studied in brain and neurons. PD patients display visual symptoms; however, the visual symptoms specifically attributed to PD patients carrying DJ-1/PARK7 mutations are not known. In this study, we analyzed the structure and physiology of retinas of 3- and 6-month-old DJ-1 knockout (KO) mice to determine how loss of function of DJ-1 specifically contributes to the phenotypes observed in PD patients. As compared to controls, the DJ-1 KO mice displayed an increase in the amplitude of the scotopic ERG b-wave and cone ERG, while the amplitude of a subset of the dc-ERG components were decreased. The main structural changes in the DJ-1 KO retinas were found in the outer plexiform layer (OPL), photoreceptors and retinal pigment epithelium (RPE), which were observed at 3 months and progressively increased at 6 months. RPE thinning and structural changes within the OPL were observed in the retinas in DJ-1 KO mice. DJ-1 KO retinas also exhibited disorganized outer segments, central decrease in red/green cone opsin staining, decreased labeling of ezrin, broader distribution of ribeye labeling, decreased tyrosine hydroxylase in dopaminergic neurons, and increased 7,8- dihydro-8-oxoguanine-labeled DNA oxidation. Accelerated outer retinal atrophy was observed in DJ-1 KO mice after selective oxidative damage induced by a single tail vein injection of NaIO3, exposing increased susceptibility to oxidative stress. Our data indicate that DJ-1-deficient retinas exhibit signs of morphological abnormalities and physiological dysfunction in association with increased oxidative stress. Degeneration of RPE cells in association with oxidative stress is a key hallmark of age-related macular degeneration (AMD). Therefore, in addition to detailing the visual defects that occur as a result of the absence of DJ-1, our data is also relevant to AMD pathogenesis.