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Abstract #66356 Published in IGR 17-3

Multipronged Approach to Identify and Validate a Novel Upstream Regulator of Sncg in Mouse Retinal Ganglion Cells

Chintalapudi SR; Morales-Tirado VM; Williams RW; Jablonski MM
FEBS Journal 2016; 283: 678-693


Loss of retinal ganglion cells (RGCs) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Mechanistic studies on RGCs are hindered by the lack of sufficient primary cells and consensus of their signature markers. Recently, γ-synuclein (SNCG) has been shown to be highly expressed in the somas and axons of RGCs. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the role of Sncg in RGCs, we used a novel systems genetics approach to identify a gene that modulates the expression of Sncg, followed by confirmatory studies in both healthy and diseased retinae. We found that chromosome 1 harbors an eQTL that modulates the expression of Sncg in the mouse retina and identified Pfdn2 as the candidate upstream modulator of Sncg expression. Our immunohistochemical analyses revealed a similar expression pattern in both mouse and human healthy retinae with PFDN2 co-localizing with SNCG in RGCs and their axons. In contrast, in retinae from glaucoma subjects, SNCG protein levels were significantly reduced, although PFDN2 levels were maintained. Using a novel flow cytometry-based RGC isolation method, we obtained viable populations of murine RGCs. Knocking down Pfdn2 expression in primary murine RGCs significantly reduced the expression of Sncg, confirming that Pfdn2 regulates Sncg expression in murine RGCs. Gene Ontology analysis indicate shared mitochondrial function associated with Sncg and Pfdn2. These data solidify the relationship between Sncg and Pfdn2 in RGCs and provide a novel mechanism for maintaining RGC health. This article is protected by copyright. All rights reserved.

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Classification:

5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
3.6 Cellular biology (Part of: 3 Laboratory methods)
11.8 Neuroprotection (Part of: 11 Medical treatment)
3.9 Pathophysiology (Part of: 3 Laboratory methods)



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