title: Retinal degeneration and ionizing radiation hypersensitivity in a mouse model for Cockayne syndrome.
abstract: Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment. CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair. This function may explain the UV sensitivity but hardly clarifies the other CS symptoms. Many of these, including retinopathy, are associated with premature aging. We studied eye pathology in a mouse model for CS. Csb(m/m) mice were hypersensitive to UV light and developed epithelial hyperplasia and squamous cell carcinomas in the cornea, which underscores the importance of transcription-coupled repair of photolesions in the mouse. In addition, we observed a spontaneous loss of retinal photoreceptor cells with age in the Csb(m/m) retina, resulting in a 60% decrease in the number of rods by the age of 18 months. Importantly, when Csb(m/m) mice (as well as Csa(-/-) mice) were exposed to 10 Gy of ionizing radiation, we noticed an increase in apoptotic photoreceptor cells, which was not observed in wild-type animals. This finding, together with our observation that the expression of established oxidative stress marker genes is upregulated in the Csb(m/m) retina, suggests that (endogenous) oxidative DNA lesions play a role in this CS-specific premature-aging feature and supports the oxidative DNA damage theory of aging.
authors.affiliation: Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Theo G M F
authors.initials: TG
authors.lastname: Gorgels
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.forename: Renata M C
authors.initials: RM
authors.lastname: Brandt
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Gerard
authors.initials: G
authors.lastname: van den Aardweg
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Jansen
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ruijter
authors.forename: Arthur A B
authors.initials: AA
authors.lastname: Bergen
authors.forename: Dirk
authors.initials: D
authors.lastname: van Norren
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003057:Cockayne Syndrome / Q000473:pathology*; D003315:Cornea / Q000166:cytology / Q000473:pathology / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000235:genetics / Q000528:radiation effects; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000473:pathology / Q000528:radiation effects; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D012162:Retinal Degeneration / Q000473:pathology*; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000235:genetics / Q000528:radiation effects
chemical_list: D000975:Antioxidants; C490652:Ckn1 protein, mouse; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011506:Proteins; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes