Light stress affects cones and horizontal cells via rhodopsin-mediated mechanisms

Samardzija, Marijana; Todorova, Vyara; Gougoulakis, Laura; Barben, Maya; Nötzli, Sarah; Klee, Katrin; Storti, Federica; Gubler, Andrea; Imsand, Cornelia; Grimm, Christian

doi:10.1016/j.exer.2019.107719

Cited by 18 publications

(22 citation statements)

References 40 publications

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“…Photooxidation causes lipofuscin accumulation, which is the oxidation byproduct of lipids and lipoproteins containing photo-oxidable fluorophores [15,16]. High levels of light-induced oxidative stress eventually triggers photoreceptor and inner retina apoptosis [17,18] and severely affects the phagocytic function of the RPE [19].…”

Section: Light-induced Oxidative Stressmentioning

confidence: 99%

“…Several studies show that both endogenous OS produced during retinal metabolism, such as lipid peroxidation or DNA damage, and exogenous OS, such as those produced by sunlight exposition, contribute to photoreceptor cell death. Moreover, rod photoreceptor death cause that higher levels of oxygen permeate into the tissue, thus increasing ROS production and inducing cell oxidative damage into the surviving cells (mostly cones), which will eventually result in cone death [17,95,96]. Since the retina is a highly-metabolic demanding tissue, retinal cells have developed protective mechanisms against damaging agents, among them, autophagy activation.…”

Section: Oxidative Stress and Retinitis Pigmentosa (Rp)mentioning

confidence: 99%

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

2020

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Retinal cell survival requires an equilibrium between oxygen, reactive oxygen species, and antioxidant molecules that counteract oxidative stress damage. Oxidative stress alters cell homeostasis and elicits a protective cell response, which is most relevant in photoreceptors and retinal ganglion cells, neurons with a high metabolic rate that are continuously subject to light/oxidative stress insults. We analyze how the alteration of cellular endogenous pathways for protection against oxidative stress leads to retinal dysfunction in prevalent (age-related macular degeneration, glaucoma) as well as in rare genetic visual disorders (Retinitis pigmentosa, Leber hereditary optic neuropathy). We also highlight some of the key molecular actors and discuss potential therapies using antioxidants agents, modulators of gene expression and inducers of cytoprotective signaling pathways to treat damaging oxidative stress effects and ameliorate severe phenotypic symptoms in multifactorial and rare retinal dystrophies.

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Section: Light-induced Oxidative Stressmentioning

confidence: 99%

Section: Oxidative Stress and Retinitis Pigmentosa (Rp)mentioning

confidence: 99%

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

2020

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“…If SFRP1 maintains photoreceptor integrity, in its absence photoreceptors should be more sensitive to a neurodegenerative stimulus. Exposure to high intensity light is an experimental paradigm widely used to induce a rhodopsin mediated www.nature.com/scientificreports www.nature.com/scientificreports/ stereotypic photoreceptor apoptosis 29 , to which cones are less susceptible 57,58 . The degree of response however varies according to the pigmentation and genetic background of the animals 29 .…”

Section: Resultsmentioning

confidence: 99%

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

Cisneros

Marco

Rueda-Carrasco

et al. 2020

Sci Rep

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Millions of individuals worldwide suffer from impaired vision, a condition with multiple origins that often impinge upon the light sensing cells of the retina, the photoreceptors, affecting their integrity. The molecular components contributing to this integrity are however not yet fully understood. Here we have asked whether Secreted Frizzled Related Protein 1 (SFRP1) may be one of such factors. SFRP1 has a context-dependent function as modulator of Wnt signalling or of the proteolytic activity of A Disintegrin And Metalloproteases (ADAM) 10, a main regulator of neural cell-cell communication. We report that in Sfrp1 −/− mice, the outer limiting membrane (OLM) is discontinuous and the photoreceptors disorganized and more prone to light-induced damage. Sfrp1 loss significantly enhances the effect of the Rpe65 Leu450Leu genetic variant-present in the mouse genetic background-which confers sensitivity to light-induced stress. These alterations worsen with age, affect visual function and are associated to an increased proteolysis of Protocadherin 21 (PCDH21), localized at the photoreceptor outer segment, and N-cadherin, an OLM component. We thus propose that SFRP1 contributes to photoreceptor fitness with a mechanism that involves the maintenance of OLM integrity. These conclusions are discussed in view of the broader implication of SFRP1 in neurodegeneration and aging. Photoreceptors are specialized neurons localized in the outermost layer of the retina, which are responsible for converting light information into electrical activity. There are two types of photoreceptors: cones that mediate vision in bright light (photopic vision), and rods that support vision in dim light (scotopic vision). Each photoreceptor develops a highly modified cilium, the outer segment (OS), composed of a stack of membranes that contains light-sensing visual pigments and other photo-transduction proteins connected to the photoreceptor cell body by the inner segment (IS). The organization, polarity and function of these specialized structures is assured at the proximal side by the presence of the outer limiting membrane (OLM), composed of a series of adherens junctions between the initial portion of the IS and the neighbouring Müller glial end-feet. At the distal side, instead, the OSs are in contact with the retinal pigment epithelium (RPE), a monolayer of cells that daily phagocyte the OS abutting portion and provides metabolic support to the photoreceptors 1. Thus, the physiology of photoreceptors is critically dependent, among others, on their interaction with adjacent non-neuronal cell types. Environmental, age-related and genetic defects disrupting these interactions lead to the progressive death of photoreceptors and thereby to the progressive loss of sight, often followed by total blindness 2. Indeed, loss of OLM integrity is commonly observed in different forms of retinal dystrophies, including Retinitis Pigmentosa (RP) 2 , a collection of monogenic disorders characterized by a tremendous genetic heterogeneity 3. Furthermore, RP c...

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“…If Sfrp1 maintains photoreceptor integrity, in its absence photoreceptors should be more sensitive to a neurodegenerative stimulus. Exposure to high intensity light is an experimental paradigm widely used to induce a rhodopsin mediated stereotypic photoreceptor apoptosis (33), to which cones are less susceptible (58,59). The degree of response however varies according to the pigmentation and genetic background of the animals (33).…”

Section: Sfrp1 Bestow Resistance To the Photoreceptors Upon Light Indmentioning

confidence: 99%

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

Cisneros

Marco

Rueda-Carrasco

et al. 2019

Preprint

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Background: Genetic and age-related photoreceptor degeneration impairs vision in millions of individuals worldwide, often enhanced by factors that modify the genotype-phenotype correlation, independently of the primary cause of the disease. Secreted Frizzled Related Protein 1 (SFRP1), a modulator of Wnt signalling and of the enzymatic activity of the αsheddase ADAM10, seems to be upregulated in human retinas affected by retinitis pigmentosa, a genetic disease leading to photoreceptors' degeneration. Here we have asked whether SFRP1 contributes to photoreceptor degeneration.Methods: Adult mice deficient in the Sfrp1 gene were used to address the implication of SFRP1 in maintaining retinal homeostasis in normal and photo-damaged conditions. Molecular and morphological preservation of the retinas was evaluated by western blot as well as histological, in situ hybridisation and immunohistochemical analysis using confocal and transmission electron microscopy. Visual function was assessed by electroretinography.Results: In Sfrp1 null mice, the outer limiting membrane (OLM) was discontinuous and the photoreceptors were disorganized and more prone to light-induced damage, significantly enhancing the effect of the Rpe65 Leu450Leu genetic variant -present in the mouse genetic background-which confers sensitivity to light-induced stress. These alterations worsened with age and led to a significant decrease in visual function. These defects were associated to an increased proteolysis of Protocadherin 21 (PCDH21), an adhesion molecule localized to the inner portion of the photoreceptor outer segment, and N-cadherin, a component of the OLM.Conclusions: SFRP1 contributes to photoreceptor fitness with a mechanism that involves the maintenance of OLM integrity. These conclusions are discussed in light of the initial observation that SFRP1 expression is upregulated in cases of retinitis pigmentosa and of the evidence that elevated levels of SFRP1 contribute to Alzheimer´s disease pathogenesis.

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Light stress affects cones and horizontal cells via rhodopsin-mediated mechanisms

Cited by 18 publications

References 40 publications

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

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

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

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