title: Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-deficient mice.
abstract: UCH-L3 belongs to the ubiquitin C-terminal hydrolase family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. A murine Uchl3 deletion mutant displays retinal degeneration, muscular degeneration, and mild growth retardation. To elucidate the function of UCH-L3, we investigated histopathological changes and expression of apoptosis- and oxidative stress-related proteins during retinal degeneration. In the normal retina, UCH-L3 was enriched in the photoreceptor inner segment that contains abundant mitochondria. Although the retina of Uchl3-deficient mice showed no significant morphological abnormalities during retinal development, prominent retinal degeneration became manifested after 3 weeks of age associated with photoreceptor cell apoptosis. Ultrastructurally, a decreased area of mitochondrial cristae and vacuolar changes were observed in the degenerated inner segment. Increased immunoreactivities for manganese superoxide dismutase, cytochrome c oxidase I, and apoptosis-inducing factor in the inner segment indicated mitochondrial oxidative stress. Expression of cytochrome c, caspase-1, and cleaved caspase-3 did not differ between wild-type and mutant mice; however, immunoreactivity for endonuclease G was found in the photoreceptor nuclei in the mutant retina. Hence, loss of UCH-L3 leads to mitochondrial oxidative stress-related photoreceptor cell apoptosis in a caspase-independent manner. Thus, Uchl3-deficient mice represent a model for adult-onset retinal degeneration associated with mitochondrial impairment.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Yae
authors.initials: Y
authors.lastname: Sano
authors.forename: Akiko
authors.initials: A
authors.lastname: Furuta
authors.forename: Rieko
authors.initials: R
authors.lastname: Setsuie
authors.forename: Hisae
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yu-Lai
authors.initials: YL
authors.lastname: Wang
authors.forename: Mikako
authors.initials: M
authors.lastname: Sakurai
authors.forename: Jungkee
authors.initials: J
authors.lastname: Kwon
authors.forename: Mami
authors.initials: M
authors.lastname: Noda
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000502:physiology*; D010786:Photoreceptor Cells / Q000166:cytology / Q000473:pathology*; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000201:enzymology / Q000473:pathology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: D043222:Ubiquitin Thiolesterase