Loss of DJ-1 elicits retinal abnormalities, visual dysfunction, and increased oxidative stress in mice

被引:43
作者
Bonilha, Vera L. [1 ,2 ]
Bell, Brent A. [2 ]
Rayborn, Mary E. [2 ]
Yang, Xiaoping [2 ]
Kaul, Charlie [2 ]
Grossman, Gregory H. [2 ]
Samuels, Ivy S. [2 ,3 ]
Hollyfield, Joe G. [1 ,2 ]
Xie, Chengsong [4 ]
Cai, Huaibin [4 ]
Shadrach, Karen G. [2 ]
机构
[1] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Ophthalmol, Cleveland, OH 44106 USA
[2] Cleveland Clin, Cole Eye Inst, Dept Ophthalm Res, Cleveland, OH 44106 USA
[3] Louis Stokes Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA
[4] NIA, Neurogenet Lab, Bethesda, MD 20892 USA
关键词
DJ-1; knockout; Retina; Morphology; Physiology; Histology; Immunohistology; Biochemistry; Oxidation; LIGHT-EVOKED RESPONSES; PARKINSONS-DISEASE; PIGMENT-EPITHELIUM; DROSOPHILA DJ-1; GEOGRAPHIC ATROPHY; ANTIOXIDATIVE STRESS; DOPAMINERGIC-NEURONS; DJ-1-DEFICIENT MICE; BRUCHS MEMBRANE; AGING CHANGES;
D O I
10.1016/j.exer.2015.07.014
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
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 was 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. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码:22 / 36
页数:15
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