title: Loss of DJ-1 elicits retinal abnormalities, visual dysfunction, and increased oxidative stress in mice.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: bonilhav@ccf.org.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Bonilha
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Bell
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rayborn
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Charlie
authors.initials: C
authors.lastname: Kaul
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Grossman
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA; Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA.
authors.forename: Ivy S
authors.initials: IS
authors.lastname: Samuels
authors.affiliation: Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA; Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Joe G
authors.initials: JG
authors.lastname: Hollyfield
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Karen G
authors.initials: KG
authors.lastname: Shadrach
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D005838:Genotype; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000071617:Protein Deglycase DJ-1; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D015398:Signal Transduction
chemical_list: D015513:Oncogene Proteins; D004247:DNA; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1
keywords: Biochemistry; DJ-1 knockout; Histology; Immunohistology; Morphology; Oxidation; Physiology; Retina