The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration

Abstract

Sorsby Fundus Dystrophy (SFD) is a rare inherited autosomal dominant macular degeneration caused by specific mutations in TIMP3 . Patients with SFD present with pathophysiology similar to the more common Age-related Macular Degeneration (AMD) and loss of vision due to both choroidal neovascularization and geographic atrophy. Previously, it has been shown that RPE degeneration in AMD is due in part to oxidative stress. We hypothesized that similar mechanisms may be at play in SFD. The objective of this study was to evaluate whether mice carrying the S179C -Timp3 mutation, a variant commonly observed in SFD, showed increased sensitivity to oxidative stress. Antioxidant genes are increased at baseline in the RPE in SFD mouse models, but not in the retina. This suggests the presence of a pro-oxidant environment in the RPE in the presence of Timp3 mutations. To determine if the RPE of Timp3 mutant mice is more susceptible to degeneration when exposed to low levels of oxidative stress, mice were injected with low doses of sodium iodate. The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice. These studies suggest that TIMP3 mutations may result in a dysregulation of pro-oxidant—antioxidant homeostasis in the RPE, leading to RPE degeneration in SFD.

Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium

“…That human SFD RPE are more vulnerable to oxidative stress complements recent findings that RPE in the SFD (S179C TIMP3) mouse model are in a pro-oxidant environment and are sensitive to low doses of an oxidizing agent (Wolk et al, 2020).…”

“…A recent in vivo study of a different SFD-associated TIMP3 mutation (S179C) murine model supports this finding, as low doses of sodium iodate, an oxidizing agent, resulted in RPE and photoreceptor degeneration. [46] Disruption of ECM homeostasis likely results in an environment of increased oxidative stress that contributes to disease onset and progression.…”

“…However, findings differ as to whether SFD iPSC RPE recapitulate important features of the disease in culture, including increased drusenoid deposits or disrupted extracellular matrices. Recently, it was shown that the S179C TIMP3 mouse model may be more susceptible to retinal degeneration after exposure to oxidative stress (Wolk et al, 2020). However, it has not been similarly shown whether human SFD RPE may have increased susceptibility to oxidative stress or alterations in metabolism.…”

Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway

“… 3 , 4 The senescence of RPE cells will impair its phagocytosis and barrier function, along with abnormal secretion of neurotrophic and angiogenic factors. 5 , 6 Therefore, clarifying the mechanism of RPE cell senescence will help to deepen the understanding of the pathological mechanisms of retinal degenerative diseases, and thus provide clues for the new drugs development for retinal disease, which remains a major problem that needs to be solved urgently.…”

Grape Seed Proanthocyanindin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway

“…RPE was a polygonal cell layer located between the choroid and the neuroretina and its dysfunction was regarded as the key factor leading to the occurrence of AMD, DR and RP [3,4]. The senescence of RPE cells would impair its phagocytosis and barrier function, along with abnormal secretion of neurotrophic and angiogenic factors [5]. Therefore, clarifying the mechanism of RPE cell senescence will help to deepen the understanding of the pathogenesis of retinal degenerative diseases, and thus provide clues for the development of new drugs for related diseases, which was a major problem that needs to be solved urgently.…”