Investigation of the role of melanosomes and radicals in photoreceptor disc clearance by the retinal pigment epithelium

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URI: http://hdl.handle.net/10900/133382
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1333827
http://dx.doi.org/10.15496/publikation-74735
Dokumentart: Dissertation
Date: 2023-11-30
Source: Parts of the dissertation presented here have already appeared in the following publications: Yanan Lyu, Alexander V. Tschulakow, Ulrich Schraermeyer. Melanosomes degrade lipofuscin and precursors that are derived from photoreceptor membrane turnover in the retinal pigment epithelium—an explanation for the origin of the melanolipofuscin granule. bioRxiv 2022.02.16.480523; doi: https://doi.org/10.1101/2022.02.16.480523.
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Schraermeyer, Ulrich (Prof. Dr.)
Day of Oral Examination: 2022-11-14
DDC Classifikation: 610 - Medicine and health
Keywords: Melanin , Elektronenmikroskopie
Other Keywords:
Stargardt disease
age-related macular degeneration
lipofuscin
radicals
License: Publishing license excluding print on demand
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Inhaltszusammenfassung:

Dissertation ist gesperrt bis 30.11.2023 !

Abstract:

Lipofuscin granules accumulate within the human RPE cell with age. The accumulation procedure is especially accelerated among Stargardt disease and age‐related macular degeneration (AMD). Another pigment granule - melanolipofuscin (MLF) starts to accumulate throughout the pathogenic procedure and aging, indicating the reduction in the capacity to degrade lipofuscin. Studies have shown the major lipofuscin amount differs between pigmented and albino Abca4-/- mice as well as non-white people and white people. Lipofuscin accumulation is ameliorated by drugs that generate superoxide (O2•-), and melanin together with superoxide and nitric oxide was discovered to be able to excite melanin electrons to a high-energy state for chemical reactions. Therefore, the present study was designed to test whether melanin is required for the photoreceptor disc clearance in the RPE and whether drugs generating NO• enhance this process. The Abca4-/- mice - models for Stargardt disease and for lipofuscin-related diseases were used in this study. Subretinal injection of the adenovirus tyrosinase vector was performed to induce melanin formation in the albino Abca4-/- mouse. Additionally, intravitreous injections of reagents (3-morpholinosydnonimine (SIN-1) or isosorbide dinitrate (ISDN)) and horseradish peroxidase that generate radicals were performed in both pigmented and albino Abca4-/- mice. Fundoscopy was measured in vivo, and electron microscopy, fluorescence microscopy, and immunofluorescence stain were used in the method. This study demonstrated the unique thin lamellar membranes (TLM) that are more often found in the albinos Abca4-/- mice than in the pigmented mice, It also showed that these TLMs originate from incomplete digestion of photoreceptor disc membranes. The results also provided an explanation of the formation of MLF - it originates from the inability of melanin to continue to degrade bisretinoids because melanin is aged or the amount of bisretinoids is overwhelmed as in Stargardt disease. Melanogenesis in adult mammal RPE after birth by adenoviral tyrosinase vector was presented. The newly formed melanin granules were near-infrared positive and oxidized within 2 weeks. And the reduction of lipofuscin was detected in the area where melanin was newly formed. The results showed a marked decrease in lipofuscin amount in the RPE cell of pigmented Abca4-/- mice after SIN-1, ISDN, or peroxidase treatments. By contrast, neither SIN-1 nor peroxidase was able to remove lipofuscin from albino Abca4-/- mice. Therefore, the current study showed a natural mechanism by which lipofuscin in RPE cells can be degraded with the support of melanosomes, and this pathway can be enhanced by drugs generating superoxide or nitric oxide.

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