2024-12-03 カリフォルニア大学校アーバイン校(UCI)
<関連情報>
- https://news.uci.edu/2024/12/03/uc-irvine-co-led-study-finds-dna-damage-is-key-factor-in-age-related-macular-degeneration/
- https://onlinelibrary.wiley.com/doi/10.1111/acel.14419
XFEプロジェロイド症候群のErcc1-/Δマウスモデルは網膜変性が加速する The Ercc1-/Δ mouse model of XFE progeroid syndrome undergoes accelerated retinal degeneration
Akilavalli Narasimhan, Seok Hong Min, Laura L. Johnson, Heidi Roehrich, William Cho, Tracy K. Her, Caeden Windschitl, Ryan D. O’Kelly, Luise Angelini, Matthew J. Yousefzadeh …
Aging Cell Published: 27 November 2024
DOI:https://doi.org/10.1111/acel.14419
Abstract
Age-related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age-related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1-XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1-/Δ mice, which models a human progeroid syndrome, were compared to age-matched wild-type (WT) and old WT mice. By 3-months-of age, Ercc1-/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1-/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ-H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1-/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age-related retinal degeneration.
