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Telomerase in Age-Related Macular Degeneration
Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan.
2. Age-Related Macular Degeneration
The pathogenesis of AMD is not completely known and many factors, both genetic/epigenetic and environmental/lifestyle-based, are involved. Oxidative stress is associated with AMD, but it is not exactly known what the source of such stress is and, in some cases, whether it belongs to the causes or consequences of the disease. Furthermore, oxidative stress can be linked with several putative or established AMD risk factors, including aging, smoking, blue light, obesity, and a diet rich in fat and carbohydrates . The retina belongs to the most metabolically active tissues in humans with the highest oxygen consumption, resulting in the production of reactive oxygen species (ROS) as byproducts of retinal metabolism . Likewise, aging, as per its definition as the main AMD risk factor, is associated with oxidative stress . Also, mitochondria, the main source of energy and ROS production, may be central for AMD pathogenesis .
3. Telomeres and Telomerase in AMD
Telomeres are DNA–protein complexes at the ends of linear chromosomes in eukaryotes. They protect chromosomes against cellular exonucleases and prevent their recognition as a DNA double-strand break by DNA damage response (DDR) and chromosomal fusion. Telomerase is an RNA-dependent DNA polymerase, which does not require an exogenous template to synthesize DNA.
Drigeard Desgarnier et al. analyzed the length of telomeres in different structures of the human eye . They found that neural retina had the longest telomeres, whereas the cornea had the shortest. The length of telomeres in RPE cells was about four times shorter than in the neural retina. These authors did not observed either age-dependent telomere attrition in the retina or any difference in the telomere length between the macula and the rest of the retina.
High content of guanine in telomeric DNA may have at least two consequences. The first is the natural tendency of single-stranded, guanine-rich DNA to fold onto itself to form four-stranded structures due to the ability of guanine to form highly stable hydrogen bonds with other guanines—guanine quartets . This property is important in the context of telomerase action, as four-stranded DNA is not a substrate for that enzyme. The second consequence follows from the fact that guanine has the highest number of oxidation-sensitive sites among all DNA bases . Therefore, telomeres may be remarkably prone to oxidative stress, a common factor of AMD pathogenesis.
4. Senescence, DNA Damage Response, and Autophagy May Underline the Involvement of Telomerase in AMD
Reactive oxygen species produced in oxidative stress may damage DNA and other biomolecules, including those important for DDR . Therefore, impaired DDR may contribute to AMD pathogenesis. Furthermore, oxidative stress and ROS induce stress-induced senescence, different from replicative senescence, but with an even worse outcome . As AMD belongs to the category of proteinopathies, disorders in which protein debris are formed, impaired autophagy is associated with AMD, but the mechanisms underlying this association are still incompletely known . Telomerase is, per its definition, engaged in preventing replicative senescence and is reported to be involved in DDR and autophagy.
There is a direct association between senescence and telomerase—telomerase prevents senescence in proliferating cells, extending their telomeres and protecting the cells against deletion in essential genes. Moreover, telomerase may extend telomeres that are shortened due to oxidative stress or any other stress resulting in telomere-associated DNA or protein damage.
4.2. DNA Damage Response
Oxidative stress is associated with overproduction of ROS, which may damage cellular macromolecules, including DNA. Oxidative stress damages telomeres, as their DNA is guanine-rich, and this is why they may be more susceptible to oxidative DNA damage than the “average” DNA in the rest of chromosomes.
Telomerase may protect the cell against DNA damage through various mechanisms. Saretzki’s lab showed that overexpression of hTERT in human fibroblasts resulted in a decrease in mtDNA damage induced by oxidative stress . To search for the mechanism underlying the observed changes, they showed that telomerase did not seem to increase the repair of mtDNA damaged by oxidative stress but induced an mitochondrial antioxidant defense mechanism . Altogether, these results show that mitochondrial telomerase may protect nuclear DNA (nDNA) from oxidative stress-induced damage by decreasing mitochondrially produced ROS, which was directly shown for cancer cells . However, it was demonstrated that ectopic expression of hTERT in human primary fibroblasts improved the kinetics of nDNA repair, likely due to an increase in the ATP level  (Figure 3).
In summary, telomerase activates/stimulates autophagy through mTORC1 inhibition that may delay aging and age-related pathologies, including AMD. Telomerase may specifically activate mitophagy by regulation of the PINK1 protein. Although several independent studies show autophagy activation by telomerase, the exact mechanism of this activation is unknown and HK2 can lie between telomerase and autophagy (Figure 4).
5. PGC-1α May Link Telomerase with AMD
The entry is from 10.3390/ijms22137194
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