MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Abstract

Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.B lindness due to photoreceptor loss from a number of diseases is a prevalent and devastating condition in the human population. Genetic predisposition and environmental stress play major roles in the incidence and progression of the retinal degeneration. Understanding disease mechanisms and interactions of causative factors should help in the design of treatment strategies. Recent evidence indicates that oxidative stress, contributing to photoreceptor cell death, plays a significant role in the pathophysiology of nonsyndromic retinitis pigmentosa (RP) and possibly age-related macular degeneration (AMD) (1-3). Moreover, light-induced oxidative stress is known to potentiate photoreceptor loss in genetic models mimicking a number of human retinal degenerations (4-11).The oxidizing microenvironment of the retinal pigment epithelium (RPE)-photoreceptor complex has been predominantly attributed to high oxygen demand, abundant polyunsaturated fatty acids, and direct exposure to light, coupled with the adjacent choroidal hemodynamics (12). Light exposure compounded over many years in the presence of photosensitizers may prime photoreceptors and RPE for free radical/oxidative damage (12-14). In some animal models of photoreceptor degeneration, including RP and Leber congenital amaurosis, disease progression is accelerated by exposure to light and slowed by rearing in darkness (3, 15). Advanced age also compromises the endogenous antioxidant ...

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

“…On the other hand, rare genetic mutations can cause specific sensitivity to oxidative and light stress in the retina. At least in mice, haploinsufficiency of Mef2d renders photoreceptors more susceptible to light-induced damage because they are unable to up-regulate Nrf2 upon oxidative stress [72]. Besides, and at least in vitro, SEMA4A mutations make RPE cells more susceptible to light irradiation, ROS and ER stress [73].…”

Light-Induced Lipocalin 2 Facilitates Cellular Apoptosis by Positively Regulating Reactive Oxygen Species/Bim Signaling in Retinal Degeneration

“…Oxidative stress has been implicated as a major player in neuronal degeneration after LE. 20,21 To determine whether LCN2 plays a role in the oxidative stress levels in light-exposed retinas, in situ ROS generation was assessed with DHE staining in freshly prepared retinal sections. Compared with the controls, the intensity of oxidized DHE fluorescence increased markedly in the retinas after LE, particularly in the ONL, whereas LCN2 knockdown clearly mitigated ROS production, evident as reduced fluorescence intensity (Figs.…”

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

“…The transcription factor Nrf2 exhibits antioxidant and anti-inflammatory properties in several tissues including the retina. Activation of Nrf2 through carnosic acid prevents retinal degeneration in Mef2d mice exposed to light damage [136]. Analogs of progesterone, which regulate Nrf2, also prevent retinal degeneration in inherited or light-damage models of retinal degeneration.…”