SOD2 knockdown mouse model of early AMD
Open accessAbstract
PURPOSE: To test the hypothesis that oxidative injury to the retinal pigment epithelium (RPE) may lead to retinal damage similar to that associated with the early stages of age-related macular degeneration (AMD). METHODS: A ribozyme that targets the protective enzyme manganese superoxide dismutase (MnSOD) was expressed in RPE-J cells, and adeno-associated virus (AAV) expressing the ribozyme gene was injected beneath the retinas of adult C57BL/6 mice. The RPE/choroid complex was examined for SOD2 protein levels and protein markers of oxidative damage using immunoblot analysis and LC MS/MS-identification of proteins and nitration sites. Lipids were extracted from retinal tissue and analyzed for the bis-retinoid compounds A2E and iso-A2E. The mice were analyzed by full-field electroretinography (ERG) for light response. Light and electron microscopy were used to measure cytological changes in the retinas. RESULTS: The treatment of RPE-J cells with Rz432 resulted in decreased MnSOD mRNA and protein as well as increased levels of superoxide anion and apoptotic cell death. When delivered by AAV, Rz432 reduced MnSOD protein and increased markers of oxidative damage, including nitrated and carboxyethylpyrrole-modified proteins in the RPE-choroid of mice. Ribozyme delivery caused a progressive loss of electroretinograph response, vacuolization, degeneration of the RPE, thickening of Bruch's membrane, and shortening and disorganization of the photoreceptor outer and inner segments. Progressive thinning of the photoreceptor outer nuclear layer resulted from apoptotic cell death. Similar to the eyes of patients with AMD, ribozyme-treated eyes exhibited increased autofluorescence and elevated levels of A2E and iso-A2E, major bis-retinoid pigments of lipofuscin. CONCLUSIONS: These results support the hypothesis that oxidative damage to the RPE may play a role in some of the key features of AMD.
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Mice with mutations making them prone to oxidative stress or dysregulation of the complement pathway have been presented as models of AMD.
“and mice with mutations making them prone to oxidative stress or dysregulation of the complement pathway have been presented as models of AMD (Imamura et al., 2006; Justilien et al., 2007; Hollyfield et al., 2008; Ufret-Vincenty et al., 2010).”
From Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis (2015) · cites this paper as Justilien et al., 2007
Sod2 knockdown mice had RPE and Bruch's membrane changes and accumulated A2E and lipofuscin granules in the RPE.
“The Sod2 knockdown mice had RPE and Bruch’s membrane changes and accumulated A2E and lipofuscin granules in the RPE (Justilien et al., 2007).”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Justilien et al., 2007
ERG a-wave and b-wave amplitudes decreased by 33% and 41%, respectively, after 4 months in Sod2 knockdown mice.
“ERG a-wave and b-wave amplitudes were noted to decrease by 33% and 41%, respectively, after 4 months.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Justilien et al., 2007
After 4 months, there was a 40% increase in Bruch's membrane thickness, specifically in the inner and outer collagenous zones, in Sod2 knockdown mice compared to age-matched wild-type mice.
“After 4 months, there was a 40% increase in Bruch’s membrane thickness, specifically in the inner and outer collagenous zones, in Sod2 knockdown mice compared to age-matched wild-type mice.”
From Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD) (2010) · cites this paper as Justilien et al., 2007
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References 72 · Cited by 234
Research works printed but not linked: 5
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- Authors
- Justilien, V., Pang, J.-J., Renganathan, K., Zhan, X., Crabb, J. W., Kim, S. R., Sparrow, J. R., Hauswirth, W. W., & Lewin, A. S.
- Affiliations
- University of Florida (US)
- Ophthalmology University of Florida, Gainesville, Florida;
- Cleveland Clinic (US)
- Columbia University (US)
- From the Departments of Molecular Genetics and
- ORCID
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2007-10-01
- Volume
- 48
- Issue
- 10
- Pages
- 4407
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC6549721
- OpenAlex
- W1978437552
- Cited by
- 234
- References
- 72
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 10 · 2023: 17 · 2022: 4 · 2021: 16 · 2020: 10 · 2019: 6 · 2018: 6 · 2017: 26 · 2016: 17 · 2015: 13 · 2014: 15 · 2013: 11 · 2012: 19
- FWCI
- 10.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (EY 13729, R01EY012951, EY 12951, EY 08571, EY 15638, U10EY013729, R01EY020825, EY016073, EY 14239, P30EY008571, R01EY016073, R01EY011123, R24EY015638, R01EY014239, EY-11123)
- National Institute of Neurological Disorders and Stroke (NS 36302, P01NS036302)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- age-related macular degeneration, manganese superoxide dismutase, ribozymes, retinal pigment epithelium, oxidative stress, A2E, lipofuscin, photoreceptor degeneration, apoptosis, superoxide, AAV gene delivery
- MeSH terms
- Superoxide Dismutase 2, Dependovirus, Animals, Disease Models, Animal, Electroretinography, Genetic Vectors, Macular Degeneration, Mice, Inbred C57BL, Mice, Inbred DBA, Photic Stimulation, Pigment Epithelium of Eye, Pyridinium Compounds, Retina, Retinoids, RNA, Messenger, Superoxide Dismutase, RNA, Catalytic, Apoptosis, Mice, Knockout, Oxidative Stress, Gene Silencing, Mice, Tandem Mass Spectrometry
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