Epigenetics in age-related macular degeneration: new discoveries and future perspectives

Gemenetzi, M; Lotery, Andrew

doi:10.1007/s00018-019-03421-w

Cited by 24 publications

(29 citation statements)

References 126 publications

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“…The environmental factors include smoking, obesity, and dietary factors [ 10 ]. Epigenetic mechanisms can alter gene expression through regulating DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Suppression of choroidal neovascularization by silencing of long non-coding RNA IPW

Yang

Yao

Sun

et al. 2021

Aging

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Long noncoding RNAs (lncRNAs) have emerged as the key regulators in the pathogenesis of human disorders. This study aimed to investigate the role of lncRNA-IPW in the progression of choroidal neovascularization (CNV) and the underlying molecular mechanism. IPW was significantly up-regulated in the choroidal tissues of laser-induced CNV mice and in the endothelial cells in response to hypoxic stress. IPW silencing led to reduced formation of CNV in laser-induced CNV model and ex vivo choroidal sprouting model, which could achieve similar therapeutic effects of anti-VEGF on CNV formation. Silencing or transgenic overexpression of IPW could alter endothelial cell viability, proliferation, migration, and tube formation ability in vitro . Mechanistically, IPW silencing led to increased expression of miR-370. Increased miR-370 could mimic the effects of IPW silencing on CNV formation and endothelial angiogenic phenotypes in vivo and in vitro . This study suggests that IPW silencing is a promising strategy for the treatment of neovascular ocular diseases.

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Section: Introductionmentioning

confidence: 99%

Suppression of choroidal neovascularization by silencing of long non-coding RNA IPW

Yang

Yao

Sun

et al. 2021

Aging

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“…Genetically con rmed that monozygotic twins can present initially with similar early macular pathology, but in the late stages of the disease, they can display different phenotypes [3]. Epigenetic mechanisms may explain some of the phenotypic variability in AMD.…”

Section: Introductionmentioning

confidence: 99%

FTO alleviates Aβ1-40 induced retinal pigment epithelium degeneration via PKA/CREB signaling pathway

Hu¹,

Chen²,

Sun³

et al. 2020

Preprint

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Background Amyloid-β (Aβ), a component of age-related macular degeneration (AMD) hallmark drusen, induces retinal pigment epithelium (RPE) cell degeneration and promotes the progress of AMD. Evidence shows that epigenetics mechanism is involved in the regulation of AMD. In this study, we aimed to investigate the roles of N6-methyladenosine (m6A) and its demethylase the fat mass and obesity-associated gene (FTO) in Aβ-mediated degeneration. Methods The molecular characteristics and morphology of FTO were examined by quantitative Real-Time PCR (qRT-PCR), Western blot and immunofluorescence. Inhibition of FTO was conducted to analyze its function on cell survival. Ocular Coherence Tomography and Fundus Photography was performed to evaluate the fundus of animal models. m6A-mRNA Epi-transcriptomic microarray, bioinformatics analysis and experimental verification were used to explore the potential molecular mechanism and signaling pathway. Results We found overexpression of FTO in Aβ model and demonstrated that inhibition of FTO by the sodium form of Meclofenamic acid (MA1) aggravated RPE impairment. Mechanistically, we identified protein kinase A (PKA) as FTO’s mediating target and found that FTO epigenetically demethylated PKA mRNA and decreased PKA expression, leading to suppressed PKA/ cyclin AMP-responsive element binding (CREB) signaling pathway. Moreover, inhibition of FTO promoted PKA/CREB signaling pathway inducing greater RPE degeneration and death. Conclusions These data demonstrated the functional significance of FTO in Aβ-induced RPE degeneration and the regulatory mechanism of PKA/CREB signaling pathway, implying FTO as a potentially therapeutic target for AMD.

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“…A strong genetic association in AMD pathogenesis was found for complement factor H (CFH) and complement factor I (CFI), as well as in the metalloproteinases tissue inhibitor 3 (TIMP3), due to the presence of rare coding variants (frequency < 0·1%) ( Mitchell et al, 2018 ). Gene–environment interaction and factors such as age and race may lead to oxidative damage and inflammation ( Sacca et al, 2009 ; Gemenetzi and Lotery, 2020 ). Strong association between several environmental factors and AMD has been reported and particularly the main demographic/environmental risk factors are aging, smoking, diet, fat intake, and obesity ( Klein et al, 1992 ; Christen et al, 1996 ; Seddon et al, 1996 ; Cho et al, 2001 ; Seddon et al, 2003 ; Friedman et al, 2004 ).…”

Section: Retinal Diseases: the Mechanisms Behind Clinical Manifestatimentioning

confidence: 99%

“…Vitrectomy followed by ERM peel-off is the routine surgical approach. Nevertheless, ERMs and even the associated internal limiting membrane can reform due to genetic/epigenetic influences or particular conditions ( Gemenetzi and Lotery, 2020 ).…”

Section: Retinal Diseases: the Mechanisms Behind Clinical Manifestatimentioning

confidence: 99%

Biomarkers of Neurodegeneration and Precision Therapy in Retinal Disease

et al. 2021

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Vision-threatening retinal diseases affect millions of people worldwide, representing an important public health issue (high social cost) for both technologically advanced and new-industrialized countries. Overall RD group comprises the retinitis pigmentosa, the age-related macular degeneration (AMD), the diabetic retinopathy (DR), and idiopathic epiretinal membrane formation. Endocrine, metabolic, and even lifestyles risk factors have been reported for these age-linked conditions that represent a “public priority” also in this COVID-19 emergency. Chronic inflammation and neurodegeneration characterize the disease evolution, with a consistent vitreoretinal interface impairment. As the vitreous chamber is significantly involved, the latest diagnostic technologies of imaging (retina) and biomarker detection (vitreous) have provided a huge input at both medical and surgical levels. Complement activation and immune cell recruitment/infiltration as well as detrimental intra/extracellular deposits occur in association with a reactive gliosis. The cell/tissue aging route shows a specific signal path and biomolecular profile characterized by the increased expression of several glial-derived mediators, including angiogenic/angiostatic, neurogenic, and stress-related factors (oxidative stress metabolites, inflammation, and even amyloid formation). The possibility to access vitreous chamber by collecting vitreous reflux during intravitreal injection or obtaining vitreous biopsy during a vitrectomy represents a step forward for an individualized therapy. As drug response and protein signature appear unique in each single patient, therapies should be individualized. This review addresses the current knowledge about biomarkers and pharmacological targets in these vitreoretinal diseases. As vitreous fluids might reflect the early stages of retinal sufferance and/or late stages of neurodegeneration, the possibility to modulate intravitreal levels of growth factors, in combination to anti-VEGF therapy, would open to a personalized therapy of retinal diseases.

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Epigenetics in age-related macular degeneration: new discoveries and future perspectives

Cited by 24 publications

References 126 publications

Suppression of choroidal neovascularization by silencing of long non-coding RNA IPW

Suppression of choroidal neovascularization by silencing of long non-coding RNA IPW

FTO alleviates Aβ1-40 induced retinal pigment epithelium degeneration via PKA/CREB signaling pathway

Biomarkers of Neurodegeneration and Precision Therapy in Retinal Disease

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