Age-Related Expression of Beta-Synuclein in the Ascending Visual Pathway and Comparative Analysis of its Function within the Neuroretina and Cerebral Cortex In-vitro

Objective: Aging hampers visual function in a multifactorial manner and the underlying perceptual deficits cannot be explained by anatomical alterations of the eye and/or visual cortex alone. The aging process of structures of the Ascending Visual Pathway (AVP) between neuroretina and visual cortex is rarely studied. The age-related increase of Beta-Synuclein (SNCB) was detected in both the neuroretina and the visual cortex (V1) in different species. SNCB acts as a physiological antagonist to neurodegenerative disease -associated alpha-synuclein. The aim of the work was to explore expression patterns of SNCB within different parts of the AVP. Further, the role of SNCB in different targeted neuronal tissues was studied. Methods: The expressions of SNCB were compared in the newborn, juvenile, adult, and aged Optic Chiasm (OC), Tracuts Opticus (TO), Laterale Geniculate Nucleus (LGN), and superior colliculus (LGN) of rats. Western blot (WB), quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and immunohistochemistry (IHC) analyses were employed to determine whether the changes identified by proteomics were verifiable at the cellular and molecular levels. To investigate the properties of SNCB in neuronal and glial cells, rat retinal and cortical samples (P5-7) were prepared and exposed to different SNCB concentrations up to 72 h in-vitro. The suspected influence on the expression on neuronal cells (e.g., beta III tubulin) and glial cell (e.g., glial fibrillary acidic protein) as well as apoptosis markers (e.g., TUNEL) was assessed by IHC, WB, and qRT-PCR. In addition, the p53-MDM2 signalling pathway was studied by IHC. Results: An increase of SNCB expression was detected in all examined regions of the AVP. Main differences of SNCB expression regarding to associated cell types were found in OC and TO in comparison to LGN and SC. The detected protein alterations in OC and TO were analogous to recent reports of the retinal profiles, while the SNCB expression characteristics in LGN and SC were more comparable to the characteristics within cortical tissues. Differences in response to SCNB exposure were found between retinal and cortical cells in-vitro. A loss of neuronal cells together with an increased apoptosis has been found in retinal cultures. In contrast, cortical cells show a beneficial elevation of neuronal response after SNCB exposure. While SNCB-exposed neuroretina show an activation of the p53-MDM-2 signaling, a decreased activation of p53-MDM-2 singanling pathway in cortical cells has been found. Conclusions: This study is the first to provide evidence that SNCB expression is associated with postnatal maturation and aging in the AVP of rats. Moreover, SNCB may exert different effects on several cell subtypes within selected neuronal targets like neuroretina and cortex. The findings may indicate the role of SNCB in key functional pathways and may account for the onset and/or progression of age-related pathologies. Further studies are needed to derive an increased understanding of neurodegenerative diseases of the retina and the cortex.