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Karina Hadrian, Harut Melkonyan, Stefan Schlatt, Joachim Wistuba, Susanne Wasmuth, Arnd Heiligenhaus, Solon Thanos, Michael R. R. Böhm; Topological distribution and potential role of age-related β-synuclein in the retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3981.
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Next to age-related changes of refracting optic media and neuroretina, the retinal pigment epithelium (RPE) underlies the physiological aging process. An age-related increase of β-synuclein (SNCB) in parts of the visual system has been described. SNCB functions as an antagonist of α-synuclein (SNCA), has been found in neurodegenerative diseases and may alter apoptotic and inflammatory responses. The onset and role of SNCB in the RPE are not sufficiently known. The aim of this work was to study the distribution of SNCB in RPE of the aging marmoset Callithrix jacchus and the characterization of SNCB in the RPE in vitro.
Paraffin-embedded eyes and RPE whole mounts of C. jacchus of different ages (neonatal, adolescent, adult) were used to study the intracellular and topological occurrence of SNCB using immunofluorescence (IF). ARPE-19 cells and primary RPE cells were incubated with different concentrations (1, 50 and 500 ng/ml) of recombinant SNCB. Apoptosis (TUNEL-assay), protein-(IF) and mRNA-expression levels (qRT-PCR) of factors of the p53/MDM2-signaling cascade and inflammation- and oxidation-related genes (HMOX1, NOX4) and cytokine and chemokine level (e.g., IL-6, IL-8, MCP-1, VEGF) were investigated.
Distinct age-related alterations of the topological and intracellular distribution of SNCB have been observed in the macula compared to periphery. In the macula, SNCB is mainly present in the cell membrane, whereas in the periphery it is mainly present in the cytoplasm and nucleus. Decreased apoptosis rates together with an activation of the p53-pathway promote senescence-related processes. Increased IL-8, HMOX and NOX4 levels indicate an elevated oxidative stress and inflammatory response. Comparable findings in cellular functions, p53 cascades, and inflammatory response have been detected in the primary RPE cells. Dose-depended alterations in cellular functions presume a general biphasic effect of SNCB.
The different distribution of SNCB in the primate RPE and alterations of cellular functions in SNCB-exposed cells promote its role in the aging RPE. The observation of an endorsed inflammatory response may indicate stress-related properties of SNCB. The functional relevance of SNCB in conversion of physiological aging into pathophysiological condition shall be investigated in further studies. Supported by the German Research Foundation (DFG; BO-4661/-1)
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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