DNA damage response and autophagy in the degeneration of retinal pigment epithelial cells—Implications for age-related macular degeneration (AMD)

Hyttinen, Juha M. T.; Błasiak, Janusz; Niittykoski, Minna; Kinnunen, Kati; Kauppinen, Anu; Salminen, Antero; Kaarniranta, Kai

doi:10.1016/j.arr.2017.03.006

Cited by 62 publications

(44 citation statements)

References 190 publications

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Section: Introductionmentioning

confidence: 99%

“…Aging is associated with the presence of elevated amounts of reactive oxygen species (ROS), the accumulation of nonfunctional cellular organelles, as well as persistent DNA damage, such as double‐strand breaks and other DNA aberrations 1,2 . Over time, the DNA repair mechanisms tend to become either inadequate or incapable of repairing the increasing amount of DNA damage, resulting in impaired cellular functionality and the appearance of cellular senescence 1,2 . It is believed that the increased DNA damage along with other detrimental cellular events are causative factors in many age‐related diseases, such as Alzheimer disease, Parkinson's disease, and age‐related macular degeneration (AMD) 1,2 …”

Section: Introductionmentioning

confidence: 99%

“…Over time, the DNA repair mechanisms tend to become either inadequate or incapable of repairing the increasing amount of DNA damage, resulting in impaired cellular functionality and the appearance of cellular senescence 1,2 . It is believed that the increased DNA damage along with other detrimental cellular events are causative factors in many age‐related diseases, such as Alzheimer disease, Parkinson's disease, and age‐related macular degeneration (AMD) 1,2 …”

Section: Introductionmentioning

confidence: 99%

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Only IL‐1β release is inflammasome‐dependent upon ultraviolet B irradiation although IL‐18 is also secreted

et al. 2020

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Abbreviations: AMD, age-related macular degeneration; ASC, adaptor protein apoptosis-associated speck-like protein containing a CARD; ATP, adenosine triphosphate; CPD, cyclobutane pyrimidine dimer; ELISA, enzyme-linked immunosorbent assay; H 2 DCFDA, 2′,7′-dichlorodihydrofluorescein diacetate; IL-18, interleukin-18; IL-1α, interleukin-1α; IL-1β, interleukin-1β; KCl, potassium chloride; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; NAC, n-acetyl-cysteine; NLRP3, nucleotide-binding domain and leucine-rich repeat pyrin containing protein 3; qRT-PCR, quantitative real-time polymerase chain reaction; RFU, relative fluorescence unit; ROS, reactive oxygen species; RPE, retinal pigment epithelium; siRNA, small interfering RNA; UVB, ultraviolet B radiation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Only IL‐1β release is inflammasome‐dependent upon ultraviolet B irradiation although IL‐18 is also secreted

et al. 2020

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“…Damage to both mitochondrial and nuclear DNA has been considered to play a role in pathogenesis of AMD (Blasiak & Szaflik, 2011;Blasiak et al, 2013a;Ferrington et al, 2016). We and others have demonstrated that AMD patients displayed more evidence of DNA damage and impaired DNA repair, as compared to control individuals without vision disturbances (Hyttinen et al, 2017;Szaflik et al, 2009). There may be changes in the DNA repair capabilities in AMD patients due to mutations in DNA repair genes (Blasiak et al, 2012;Synowiec et al, 2012).…”

Section: Dna Damage Responsementioning

confidence: 86%

Can vitamin D protect against age-related macular degeneration or slow its progression?

et al. 2019

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Dietary vitamin D plays an important role in maintaining proper vision. Age-related macular degeneration (AMD) is a complex eye disease with unknown pathogenesis. Studies on dietary supplementation and AMD occurrence and progression have produced conflicting results. In its advanced stage, AMD may be associated with apoptosis, pyroptosis or necroptosis of retinal cells. Vitamin D has been reported to play a role in modulating each of these programmed death pathways. Vitamin D is a modulator of the immune system and it acts synergistically with two members of the regulators of complement activation family H and I, whose specific variants are the most important genetic factors for AMD pathogenesis. Angiogenesis is an essential component of the neovascular form of AMD, the most devastating type of the disease and vitamin D is reputed to possess antiangiogenic properties. Cellular DNA damage response is weakened in AMD patients and so it is another process that can be modulated by vitamin D. Finally, impaired autophagy is claimed to play a role in AMD and emerging evidence suggests that vitamin D can influence autophagy. Therefore, several pathways of vitamin D metabolism and AMD pathogenesis overlap, suggesting that vitamin D could modulate the course of AMD.

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“…DNA damage was evaluated by the comet assay, and the production of 8-OH-dG (8-hydroxydeoxyguanosine), which is considered as a hallmark of oxidative DNA damage and oxidative stress in general. We and others have shown that AMD patients display an impaired DDR, evidenced by enhanced levels of damage to nuclear and mitochondrial DNA and decreased efficacy of DNA repair [9,60,92,93]. However, these studies did not unequivocally show a mechanism of observed changes.…”

Section: Potential Of Pgc-1α In Amdmentioning

confidence: 93%

PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

Kaarniranta

Kajdanek

Morawiec

et al. 2018

IJMS

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PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

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DNA damage response and autophagy in the degeneration of retinal pigment epithelial cells—Implications for age-related macular degeneration (AMD)

Cited by 62 publications

References 190 publications

Only IL‐1β release is inflammasome‐dependent upon ultraviolet B irradiation although IL‐18 is also secreted

Only IL‐1β release is inflammasome‐dependent upon ultraviolet B irradiation although IL‐18 is also secreted

Can vitamin D protect against age-related macular degeneration or slow its progression?

PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

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