Decreased proteasomal activity causes photoreceptor degeneration in mice

Ryo Ando, Kousuke Noda, Utano Tomaru, Mamoru Kamoshita, Yoko Ozawa, Shoji Notomi, Toshio Hisatomi, Mika Noda, Atsuhiro Kanda, Tatsuro Ishibashi, Masanori Kasahara, Susumu Ishida

Research output: Contribution to journalArticle

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Abstract

Purpose: 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.

Original languageEnglish
Pages (from-to)4682-4690
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume55
Issue number7
DOIs
Publication statusPublished - 2014 Jul 3

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Transgenic Mice
In Situ Nick-End Labeling
Ubiquitinated Proteins
Apoptosis Inducing Factor
Photoreceptor Cells
Retinal Degeneration
Genetically Modified Animals
Caspase 9
Chymotrypsin
Caspases
Lighting
Caspase 3
Fluorescent Antibody Technique
Cell Death
Animal Models
Staining and Labeling
Proteins

Keywords

  • Neurodegeneration
  • Photoreceptor cell death
  • Proteasomal dysfunction

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Decreased proteasomal activity causes photoreceptor degeneration in mice. / Ando, Ryo; Noda, Kousuke; Tomaru, Utano; Kamoshita, Mamoru; Ozawa, Yoko; Notomi, Shoji; Hisatomi, Toshio; Noda, Mika; Kanda, Atsuhiro; Ishibashi, Tatsuro; Kasahara, Masanori; Ishida, Susumu.

In: Investigative Ophthalmology and Visual Science, Vol. 55, No. 7, 03.07.2014, p. 4682-4690.

Research output: Contribution to journalArticle

Ando, R, Noda, K, Tomaru, U, Kamoshita, M, Ozawa, Y, Notomi, S, Hisatomi, T, Noda, M, Kanda, A, Ishibashi, T, Kasahara, M & Ishida, S 2014, 'Decreased proteasomal activity causes photoreceptor degeneration in mice', Investigative Ophthalmology and Visual Science, vol. 55, no. 7, pp. 4682-4690. https://doi.org/10.1167/iovs.13-13272
Ando, Ryo ; Noda, Kousuke ; Tomaru, Utano ; Kamoshita, Mamoru ; Ozawa, Yoko ; Notomi, Shoji ; Hisatomi, Toshio ; Noda, Mika ; Kanda, Atsuhiro ; Ishibashi, Tatsuro ; Kasahara, Masanori ; Ishida, Susumu. / Decreased proteasomal activity causes photoreceptor degeneration in mice. In: Investigative Ophthalmology and Visual Science. 2014 ; Vol. 55, No. 7. pp. 4682-4690.
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AU - Noda, Kousuke

AU - Tomaru, Utano

AU - Kamoshita, Mamoru

AU - Ozawa, Yoko

AU - Notomi, Shoji

AU - Hisatomi, Toshio

AU - Noda, Mika

AU - Kanda, Atsuhiro

AU - Ishibashi, Tatsuro

AU - Kasahara, Masanori

AU - Ishida, Susumu

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AB - Purpose: 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.

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KW - Photoreceptor cell death

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