Abstract
The family of synuclein proteins (α, β and γ) are related to neurodegenerative disease e.g. Parkinson disease and Morbus Alzheimer. Additionally, a connection between γ-synuclein and glaucoma, a neurodegenerative disease characterized by a progressive loss of retinal ganglion cells, which finally leads to blindness, exists. The reason for the development of glaucoma is still unknown. Recent studies evaluating the participation of immunological components, demonstrate complex changed antibody reactivities in glaucoma patients in comparison to healthy people, showing not only up-regulations (e.g. alpha-fodrin antibody) but also down-regulations (e.g. γ-synuclein antibody) of antibodies in glaucoma patients. Up-regulated antibodies could be auto-aggressive, but the role of down-regulated antibodies is still unclear. Previous studies show a significant influence of the serum and the antibodies of glaucoma patients on protein expression profiles of neuroretinal cells. The aim of this study was to investigate the effect of γ-synuclein antibody on the viability and reactive oxygen species levels of a neuroretinal cell line (RGC-5) as well as their interaction with cellular proteins. We found a protective effect of γ-synuclein antibody resulting in an increased viability (up to 15%) and decreased reactive oxygen species levels (up to −12%) of glutamate and oxidative stressed RGC-5. These can be traced back to anti-apoptotic altered protein expressions in the mitochondrial apoptosis pathway indicated by mass spectrometry and validated by microarray analysis such as active caspase 3, bcl-2 associated-x-protein, S100A4, voltage-dependent anion channel, extracellular-signal-regulated-kinase (down-regulated) and baculoviral IAP repeat-containing protein 6, phosphorylated extracellular-signal-regulated-kinase (up-regulated). These changed protein expression are triggered by the γ-synuclein antibody internalization of RGC-5 we could see in immunohistochemical stainings. These findings let us assume a novel physiological function of γ-synuclein antibodies and give insights in the role of autoantibodies in glaucoma. We hypothesize that the down-regulation of autoantibodies found in glaucoma patients lead to a loss of protective autoimmunity.
Highlights
Synucleins are a family of small, cytosolic proteins consisting of a, b- and c-synuclein
Glaucoma is a heterogeneous neurodegenerative disease defined by a progressive loss of rgc, optic nerve degeneration and progressive visual field loss, which can lead to blindness [12]
Acetonitril (ACN), trifluoroacetic acid (TFA) and formic acid were purchased from Merck (Darmstadt, Germany), wheat germ agglutinin from Invitrogen (Carlsbad, U.S.A.) and BCA Pierce Protein Assay kit and Dylight 649 was purchased from Fisher scientific (Waltham, MA.)
Summary
Synucleins are a family of small, cytosolic proteins consisting of a-, b- and c-synuclein They are abundant in neuronal tissues [1] and associated with the pathogenesis of neurodegenerative diseases. In comparison to healthy people, the optic nerve head and retina of glaucoma patients show different c-synuclein localizations [9,11]. Previous studies incubating neuroretinal cells with the serum and the abs of glaucoma patients found changed protein expression patterns in cells incubated with glaucoma serum in comparison to serum from healthy people [19]. The cells reacted differently towards the serum after removal of IgG abs [19] These results underline the hypothesis that changes in the autoantibodies could play a role in the pathogenesis of the disease
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