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Multipronged approach to identify and validate a novel upstream regulator of Sncg in mouse retinal ganglion cells
Author(s) -
Chintalapudi Sumana R.,
MoralesTirado Vanessa M.,
Williams Robert W.,
Jablonski Monica M.
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13620
Subject(s) - biology , retinal ganglion cell , microbiology and biotechnology , neuroscience , retina
Loss of retinal ganglion cells ( RGC s) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Mechanistic studies on RGC s are hindered by the lack of sufficient primary cells and consensus regarding their signature markers. Recently, γ‐synuclein ( SNCG ) has been shown to be highly expressed in the somas and axons of RGC s. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the role of Sncg in RGC s, we used a novel systems genetics approach to identify a gene that modulates Sncg expression, followed by confirmatory studies in both healthy and diseased retinae. We found that chromosome 1 harbors an expression quantitative trait locus that modulates Sncg expression in the mouse retina, and identified the prefoldin‐2 ( PFDN 2) gene as the candidate upstream modulator of Sncg expression. Our immunohistochemical analyses revealed similar expression patterns in both mouse and human healthy retinae, with PFDN 2 colocalizing with SNCG in RGC s and their axons. In contrast, in retinae from glaucoma subjects, SNCG levels were significantly reduced, although PFDN 2 levels were maintained. Using a novel flow cytometry‐based RGC isolation method, we obtained viable populations of murine RGC s. Knocking down Pfdn2 expression in primary murine RGC s significantly reduced Sncg expression, confirming that Pfdn2 regulates Sncg expression in murine RGC s. Gene Ontology analysis indicated shared mitochondrial function associated with Sncg and Pfdn2 . These data solidify the relationship between Sncg and Pfdn2 in RGC s, and provide a novel mechanism for maintaining RGC health.