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A. P. Surguchov, K. Cain, I. Surgucheva; -Synuclein Transcriptional Regulation in Retinal Ganglion Cells and Astrocytes. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5549.
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© ARVO (1962-2015); The Authors (2016-present)
Synucleins are small highly conserved proteins in vertebrates extensively expressed in the brain and retina. α-Synuclein forms the major fibrillar components associated with the pathological lesion, and it is genetically linked with Parkinson’s diseases. According to recent gene expression profiling analysis, γ-synuclein is the second largest cluster in retinal ganglion cells (RGC) after tubulin. Synucleins are involved in the regulation of neurotransmitter release, vesicular transport and proteasomal activity. It is becoming apparent that synuclein expression levels are a major factor in the pathogenesis of neurodegenerative diseases. Alterations of γ-synuclein expression in glaucomatous retinas and effect of elevated intraocular pressure (IOP) on γ-synuclein expression was described by several investigators suggesting that γ-synuclein might be a marker for RGC loss in glaucoma. We compared mechanisms of γ-synuclein transcriptional regulation in RGC and astrocytes.
To study transcriptional regulation and identify the regulatory sequences in γ-synuclein upstream region responsible for its transcription in neuronal and glial cells we analyzed the promoter activities of the 2.2-kb genomic fragment of γ-synuclein pGL3-BCSG1-2195 and its various deletion derivatives. Seven constructs including mutated AP1 and AP2 sites and deletions in 1 intron were generated using QuickChange Site-Directed Mutagenesis Kit. RGC-5 and astrocytes were transfected by these constructs with subsequent measurement of luciferase activity by luminometer.
We found different mechanisms of transcriptional regulation of γ-synuclein gene in RGC and astrocytes. Important regulatory elements playing the role in cell type specific transcription regulation of γ-synuclein are located in intron 1 (AP-1 binding site TGACTCA located at position +612 - +628 and another AP-1 site in reverse orientation in close proximity to the first site). Other regulatory elements are located upstream from the coding sequence area. Cis-elements affecting transcription of γ-synuclein gene in cell type-nonspecific manner are also identified.
These data support the view that γ-synuclein pathology in ocular tissues described previously may be a result of misregulation of its transcription. The results are discussed in connection with possible implication of γ-synuclein in diseases and approach to modulate its expression.
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