title: Decreased proteasomal activity causes photoreceptor degeneration in mice.
abstract: OBJECTIVE
  To study the retinal degeneration caused by decreased proteasomal activity in β5t transgenic (β5t-Tg) mice, an animal model of senescence acceleration.
  
  
  METHODS
  β5t-Tg mice and age-matched littermate control (WT) mice were used. Proteasomal activities and protein level of poly-ubiquitinated protein in retinal extracts were quantified. Fundus images of β5t-Tg mice were taken and their features were assessed. For histologic evaluation, the thicknesses of inner nuclear layer (INL), outer nuclear layer (ONL), and photoreceptor outer segment (OS) were measured. For functional analysis, ERG was recorded under scotopic and photopic illumination conditions. Immunofluorescence (IF) staining and TUNEL were performed to investigate the mechanism of photoreceptor degeneration.
  
  
  RESULTS
  Chymotrypsin-like activity was partially suppressed in retinal tissues of β5t-Tg mice. Retinal degenerative changes with arterial attenuation were present in β5t-Tg, but not in WT mice. Inner nuclear layer thickness showed no significant change between β5t-Tg and WT mice at 1, 3, 6, and 9 months of age. By contrast, thicknesses of ONL and OS in β5t-Tg mice were significantly decreased at 3, 6, and 9 months compared with those in WT mice. Electroretinograms showed decrease of scotopic a-wave amplitude in β5t-Tg mice. The number of TUNEL-positive cells in ONL were significantly increased in β5t-Tg mice and colocalized with apoptosis-inducing factor, but not with cleaved caspase-3 and -9, indicating that the photoreceptor cell death was induced via a caspase-independent pathway.
  
  
  CONCLUSIONS
  The current data showed that impaired proteasomal function causes photoreceptor degeneration.
authors.affiliation: Laboratory of Ocular Cell Biology & Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ando
authors.affiliation: Laboratory of Ocular Cell Biology & Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Utano
authors.initials: U
authors.lastname: Tomaru
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kamoshita
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Notomi
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hisatomi
authors.affiliation: Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Noda
authors.affiliation: Laboratory of Ocular Cell Biology & Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Kanda
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kasahara
authors.affiliation: Laboratory of Ocular Cell Biology & Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D021122:Protein Subunits; D012160:Retina / Q000201:enzymology*; D012162:Retinal Degeneration / Q000201:enzymology* / Q000473:pathology
chemical_list: D021122:Protein Subunits; D046988:Proteasome Endopeptidase Complex; C520309:proteasome subunit beta5t, mouse
keywords: neurodegeneration; photoreceptor cell death; proteasomal dysfunction