title: Overexpression of SOD in retina: need for increase in H2O2-detoxifying enzyme in same cellular compartment.
abstract: In retinitis pigmentosa (RP), various mutations cause rod photoreceptor cell death leading to increased oxygen levels in the outer retina, progressive oxidative damage to cones, and gradual loss of cone cell function. We have been exploring the potential of overexpressing components of the endogenous antioxidant defense system to preserve cone cell function in rd10(+/+) mice, a model of RP. rd10(+/+) mice deficient in superoxide dismutase 1 (SOD1) showed increased levels of superoxide radicals and carbonyl adducts (a marker of oxidative damage) in the retina and more rapid loss of cone function than rd10(+/+) mice with normal levels of SOD1. This suggests that SOD1 is an important component of the antioxidant defense system of cones, but increased expression of SOD1 in rd10(+/+) mice increased oxidative damage and accelerated the loss of cone function. Coexpression of SOD1 with glutathione peroxidase 4 (Gpx4), which like SOD1 is localized in the cytoplasm, but not with catalase targeted to the mitochondria, reduced oxidative damage in the retina and significantly slowed the loss of cone cell function in rd10(+/+) mice. Gene transfer resulting in increased expression of SOD2, but not coexpression of SOD2 and mitochondrial Gpx4, resulted in high levels of H(2)O(2) in the retina. These data suggest that to provide benefit in RP, overexpression of an SOD must be combined with expression of a peroxide-detoxifying enzyme in the same cellular compartment.
authors: Department of Ophthalmology and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Shinichi
authors: S
authors: Usui
authors: Brian C
authors: BC
authors: Oveson
authors: Takeshi
authors: T
authors: Iwase
authors: Lili
authors: L
authors: Lu
authors: Sun Young
authors: SY
authors: Lee
authors: Young-Joon
authors: YJ
authors: Jo
authors: Zhihao
authors: Z
authors: Wu
authors: Eun-Young
authors: EY
authors: Choi
authors: Richard J
authors: RJ
authors: Samulski
authors: Peter A
authors: PA
authors: Campochiaro
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004596:Electroretinography; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology; D018384:Oxidative Stress; D010617:Phenanthridines / Q000032:analysis; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D012160:Retina / Q000201:enzymology* / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D005979:Glutathione Peroxidase; D006861:Hydrogen Peroxide; D010617:Phenanthridines; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C058428:hydroethidine