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N. Marsh-Armstrong, I. Soto, E. Oglesby, C.-H. O. Davis, E. H. Mules, F. Valiente-Soriano, M. Vidal-Sanz, V. Buchman, P. A. Watkins, J. V. Nguyen; Gamma-Synuclein Aggregation and Activation of Optic Nerve Head Astrocytes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2100.
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To evaluate whether there are gamma-synuclein aggregates in mouse glaucoma animal models, and to determine whether and how gamma-synuclein is protective or deleterious for retinal ganglion cells (RGC).
Using antibodies, the presence of gamma-synuclein aggregates was examined by immunohistochemistry and Western blotting in DBA/2J mice. Levels of Mac-2 and Adipose Differentiation Related Protein (Adrp) proteins were analyzed in optic nerve head (ONH) longitudinal sections using novel segmentation-less image analyses. The number of RGC was determined in retina wholemounts by gamma-synuclein or neurofilament light mRNA expression. The number of RGC with somatic phosphorylated neurofilament (pNF+ RGC) was used to estimate the number of RGC with axonal injuries. Intraocular pressure (IOP) was elevated in C57BL/6J mice by translimbal laser photocoagulation.
We find gamma-synuclein aggregates in the retina of aged but not young DBA/2J by immunohistochemistry and Western blotting. The earliest formation of these aggregates occurs at the myelination transition zone (MTZ) of the ONH. There, a unique set of astrocytes expressing Mac-2 and other phagocytic genes enwrap large aggregates and dramatically upregulate Mac-2 and the lipid droplet marker Adrp in aged DBA/2J. In both RGC5 cells and MTZ astrocytes, the gamma-synuclein aggregates are associated with Adrp in lipid droplets. Both Mac-2 and Adrp are also upregulated in MTZ astrocytes one week after elevation of IOP in Sncg +/- mice. Sibling Sncg -/- mice upregulate Adrp but fail to upregulate Mac-2. The Sncg -/- mice also develop twice the number of pNF+ RGC.
These studies demonstrate the presence of gamma-synuclein aggregates in two mouse models of glaucoma, indicating that glaucoma is a synucleinopathy similar to Parkinson’s disease. These studies also suggest that a previously unrecognized subpopulation of ONH astrocytes play a prominent phagocytic role in glaucoma. Further, they show that the gamma-synuclein aggregates are forms of the protein associated with lipid droplets, and that gamma-synuclein plays a protective function after acute axonal insult. These findings that are likely relevant not only to glaucoma but also to other synucleinopathies.
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